Intranasal Compositions For Treatment of Neurological And Neurodegenerative Diseases And Disorders

ABSTRACT

The present invention relates generally to intranasal pharmaceutical compositions. In particular, the present invention is directed to sustained, enhanced delivery of pharmaceutical agents across the nasal mucosa for systemic drug delivery.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/516,233, filed Mar. 31, 2017, which is a 35 U.S.C. § 371 filing ofInternational Application No. PCT/AU2015/050591, filed on Sep. 30, 2015,which claims priority to Australian patent application number2014903944, filed Oct. 3, 2014. The entire contents of theseapplications are incorporated by reference herein, in their entirety.

TECHNICAL FIELD

The present invention relates generally to intranasal pharmaceuticalcompositions. In particular, the present invention is directed tosustained, enhanced delivery of pharmaceutical agents across the nasalmucosa for systemic drug delivery. More particularly, the presentinvention relates to an intranasal composition comprising rivastigminefor the treatment of neurological and neurodegenerative diseases.

BACKGROUND

Neurological and neurodegenerative diseases and disorders representpotentially debilitating conditions and can affect people of all ages.Neurological and neurodegenerative diseases and disorders may beacquired, congenital, hereditary or sporadic conditions. They aretypically associated with widely varying degrees of difficulty which mayhave significant mental, emotional, physical, and economic consequencesfor individuals.

Neurodegenerative diseases and disorders are typically characterized byprogressive nervous system dysfunction and may be associated withatrophy of the affected central or peripheral structures of the nervoussystem. Examples of neurodegenerative diseases and disorders include butare not limited to dementia, including Alzheimer's Disease, degenerativenerve diseases, encephalitis, epilepsy, hydrocephalus, stroke,Parkinson's disease, multiple sclerosis, brain cancer, cognitivedysfunction syndrome, amyotrophic lateral sclerosis (ALS), andHuntington's disease.

The term “dementia” is often used to refer to a broad category of braindiseases characterised by a progressive decline in cognition and mentalability wherein memory, thinking, and judgement may be impaired. Thistype of neurodegenerative disease typically affects those over the ageof 60, however early onset forms of the disease are also known. It isestimated that approximately 24 million people worldwide suffer fromdementia, of which approximately 50 to 70% are estimated to be due toAlzheimer's disease.

Alzheimer's disease is a highly variable condition which presents anddevelops differently in each individual. While the cause and progressionof the disease is not well understood, there are many common symptoms.In the initial stages, sufferers often exhibit short term memory loss.As the disease progresses, symptoms may include confusion, irritability,aggression, mood swings, trouble with language, and long-term memoryloss. The later stages are often characterised by loss of bodilyfunctions which ultimately results to death.

Diagnosis of Alzheimer's disease is usually based on an evaluation ofbehaviour and cognition, however brain scans and examination of braintissue is required for a definitive diagnosis. Other neurological andneurodegenerative diseases are also associated with dementia-likesymptoms. For example, dementia commonly develops in the advanced stagesof Parkinson's disease. Furthermore, cognitive dysfunction syndrome hasbeen recognized as having similarities with Alzheimer's disease.

To date, there is no known cure for dementia or Alzheimer's disease.Current treatments include pharmaceutical and psychosocial treatments,however, no single medication or treatment is known to relieve orreverse the core symptoms of Alzheimer's disease with current treatmentstypically offering a relatively small symptomatic benefit.

A reduction in the activity of the cholinergic neurons is associatedwith Alzheimer's disease. Administration of acetylcholinesteraseinhibitors may thus be used to increase the concentration ofacetylcholine in the brain and counter the loss of acetylcholine causedby the death of cholinergic neurons. Current pharmaceutical treatmentsfor the cognitive symptoms associated with Alzheimer's disease thusinclude acetylcholinesterase inhibitors and NMDA receptor antagonists.

Rivastigmine, an acetylcholinesterase inhibitor, is currently used forthe treatment of patients suffering from neurological conditions, suchas dementia caused by Alzheimer's disease and Parkinson's disease (Birkset al. 2009; Birks et al. 2015; Maidment et al. 2006). Furthermore, theuse of cholinesterase inhibitors has been shown to help improvecholinergic function associated with other disorders, includingcognitive dysfunction syndrome (Gonzalez-Martinez A. et al. 2013; AraujoJ A. et al. 2011).

Rivastigmine has the following structure, and may also be provided as apharmaceutically acceptable salt or hydrate:

Currently, rivastigmine is available as a capsule or a solution for oraladministration and as a transdermal patch. However, the orally availableforms of rivastigmine are associated with significant side effects,including nausea, vomiting, diarrhoea and asthenia (Feldman and Lane2007; Winblad et al. 2007). Additionally, oral rivastigmine has lowabsolute oral bioavailability of about 35% at a dose of 3 mg, and athigher oral doses of 6 mg and above it exhibits non-linear oralpharmacokinetics (Hossain et al. 2002). The effective treatment ofAlzheimer's disease ideally requires central cholinesterase inhibitionin order to improve cholinergic signalling in the brain (Cutler et al.1998; Gobburu et al. 2001). However, greater peripheral cholinesteraseinhibition may also occur where higher doses of a given drug areadministered to counter low bioavailability, as is the case with oralrivastigmine. This may in turn result in a higher risk of adverse eventsand associated unwanted side effects.

While the rivastigmine transdermal patch addresses some of thesedeficiencies, it is known to cause skin irritation in a significantproportion of patients and may also disturb circadian rhythms resultingin disrupted sleep patterns (Lamer 2010; Grossberg et al. 2010; Kurz etal. 2009). Consequently, the treatment discontinuation rate for thetransdermal patch was found to be higher than the oral capsule (Winbladet al. 2007).

Accordingly, there is an on-going need to develop new methods oftreating neurodegenerative diseases and disorders, such as Alzheimer'sdisease.

SUMMARY

It has now been surprisingly found that the intranasal delivery ofacetylcholinesterase inhibitors, such as rivastigmine, may offer animproved treatment for neurodevelopmental diseases and disorders such asdementia caused by Alzheimer's disease and Parkinson's disease. Inparticular, intranasal delivery may advantageously provide enhanceddelivery of acetylcholinesterase inhibitors such as rivastigmine.

The formulations of the present invention may allow an active agent tobe absorbed in a sustained manner providing improved bioavailability atlow or reduced doses and/or longer duration of action. Advantageously,the formulations of the present invention may also provide a reducedincidence of side effects when compared with other drug deliverymethods.

Accordingly, in one aspect the present invention provides asustained-release aqueous intranasal formulation comprising rivastigmineor a pharmaceutically acceptable salt thereof, a pH modifying agent anda thickening agent, wherein pH of the formulation is in the range ofabout 3 to 6.

Intranasal drug delivery offers many advantages including rapidabsorption due to abundant capillary vessels, fast onset of action,avoidance of hepatic first-pass metabolism, and utility for chronicmedication. Additionally, aqueous intranasal formulations also provideease of administration, especially administration as an intranasalspray.

The aqueous intranasal formulations comprising rivastigmine or apharmaceutically acceptable salt thereof, a pH modifying agent and athickening agent in accordance with the invention may advantageouslyprovide a balance between ease of administration by intranasal deliveryand adherence of the formulation to the nasal mucosa. In particular, theaqueous formulations comprising rivastigmine, a pH modifying agent and athickening agent in accordance with the invention may be administered asa stable intranasal spray yet provide sufficient residence time on thenasal mucosa to allow trans-nasal absorption of the active agent.Furthermore the aqueous intranasal formulations in accordance with thepresent invention may additionally allow a low or reduced dose of anactive agent to be administered, sustained release of the active agent,longer duration of action, and/or a reduced incidence of side effectswhen compared with other drug delivery methods.

In particular, the pH modifying agent of the intranasal formulations ofthe present invention may provide or adjust the pH of the formulation toa pH in the range of about 3 to 6. It has surprisingly been found thatwhere the intranasal formulations of the present invention areformulated with a pH range of about 3 to 6, the formulation, inparticular the active agent, may exhibit increased pharmaceuticalstability. Furthermore, a pH in the range of about 3 to 6 has also beenfound to assist in solubilising the active agent in solution.

Additionally, the thickening agent of the intranasal formulations of thepresent invention may modify the viscosity of the formulation to provideimproved adherence of the formulation to the nasal mucosa withoutadversely affecting the ease of administration, in particularadministration as an intranasal spray. Without wishing to be bound bytheory, the thickening agent may additionally increase the residencetime of the formulation on the nasal mucosa, reduce loss of theformulation via mucociliary clearance of the nasal passages and/orimprove the trans-nasal absorption. Specifically, in one or moreembodiments, the thickening agent may comprise about 0.1% to about 2% byweight of the total composition.

In another aspect, the aqueous intranasal formulations in accordancewith the invention may further comprise a sensory agent. The sensoryagent in accordance with the present invention may advantageouslyprovide the patient with sensory feedback upon use, for example, thatthe intranasal formulation of the present invention has been deliveredto the correct location within the nasal passage. Furthermore, thesensory agent may also adjust the viscosity in combination with thethickening agent, to further balance the ease of administration of theformulation, in particular as an intranasal spray, with the subsequentadherence of the formulation to the nasal mucosa.

In yet another aspect, the aqueous intranasal formulations in accordancewith the invention may advantageously provide an absolutebioavailability equivalent to at least 60% of the active agent, forexample, as rivastigmine free base, where bioavailability refers to thefraction of the administered dose of the active agent that reaches thesystemic circulation (blood stream).

In a further aspect, the aqueous intranasal formulations in accordancewith the invention may further comprise an additional therapeutic agentselected from a sigma-1 receptor agonist, a NMDA antagonist, a nicotinicacetylcholine receptor agonist and combinations thereof. Where theaqueous intranasal formulations of the present invention comprisingrivastigmine are administered in combination with an additionaltherapeutic agent, such a formulation may further reduce or alleviateone or more of the core symptoms of a given neurodegenerative disorder,such as Alzheimer's disease or Parkinson's disease.

In still other aspects, the present invention provides methods oftreating neurodegenerative diseases in a mammal, comprisingadministering an intranasal formulation comprising rivastigmine or apharmaceutically acceptable salt thereof, a pH modifying agent and athickening agent, wherein the formulation has a pH in the range of about3 to 6.

In one or more embodiments, the neurodegenerative disease or disordermay be dementia caused by Alzheimer's disease and Parkinson's disease.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs.

The reference to any prior art in this specification is not, and shouldnot be taken as, an acknowledgment or any form of suggestion that thatprior art forms part of the common general knowledge.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 5 depict various diffusion profiles for nasal formulationsapplied to freshly excised, adult bovine nasal mucosa held within invitro, flow-through diffusion cells. The diffusion profiles representthe Cumulative Amount of Rivastigmine as the free base equivalent (QRiv) over time (h).

FIG. 1: Q Riv across bovine nasal mucosa (0 to 6 h) for Formulation 1 (●round symbols, n=8) and Control Formulation 4 (▪ square symbols, n=8)after a finite dose (5 μL/cm²) at 0 h.

FIG. 2: Q Riv across bovine nasal mucosa (0 to 12 h) for Formulation 1(● round symbols, n=4) and Control Formulation 4 (▪ square symbols, n=8)after a finite dose (5 μL/cm²) at 0 h.

FIG. 3: Q Riv across bovine nasal mucosa (0 to 18 h) for Formulation 1(● round symbols, n=4) and Formulation 2 (▪ square symbols, n=4) afterrepeated finite dosing (5 μL/cm²) at 0 h and 6 h.

FIG. 4: Q Riv across bovine nasal mucosa (0 to 24 h) for Formulation 3(● round symbols, n=4) after a finite dose (20 μL/cm²) at 0 h.

FIG. 5: Diagram of a flow-through diffusion cell; including nasalmucosal membrane (1); formulation on membrane surface (2); receptorsolution inlet (3); receptor solution chamber (4); receptor solutionoutlet (5); transparent viewing window (6).

FIG. 6: Mean (±SD) plasma concentration-time profiles of rivastigmineafter administration i) rivastigmine 1 mg as a constant intravenousinfusion (∘); or ii) 3.126 mg intranasal spray (●) in healthy elderlyindividuals (n=8).

FIG. 7: Mean (±SD) plasma concentration-time profiles of NAP226-90 afteradministration of i) 1 mg rivastigmine 1 mg as a constant intravenousinfusion (∘); or ii) 3.126 mg intranasal spray (●) in healthy elderlyindividuals (n=8).

DETAILED DESCRIPTION

The present invention relates to intranasal compositions for treatingneurodegenerative diseases or disorders such as dementia associated withAlzheimer's disease. In particular, the present invention relates tointranasal compositions comprising rivastigmine for treatingneurodegenerative diseases or disorders.

The present invention also relates to methods of treatingneurodegenerative diseases or disorders comprising administering to amammal in need thereof an effective amount of an intranasal compositionas described herein.

The compositions and methods of the present invention are formulated forintranasal delivery. In particular, nasal drug delivery of active agentsin accordance with the present invention offers a number of advantages,including but not limited to rapid absorption, fast onset of action,avoidance of hepatic first-pass metabolism, and ease of administration.

More particularly, the compositions and methods of the present inventionmay advantageously reduce or alleviate one or more of the core symptomsof a given neurodegenerative disorder, for example the symptoms ofdementia associated with Alzheimer's diseases or Parkinson's disease. Insome aspects, the compositions and methods of the present invention mayadvantageously enable an active agent to be absorbed in a sustainedmanner providing improved bioavailability at lower doses and/or longerduration of action. For example, in one or more embodiments, the presentinvention may provide sustained, enhanced delivery ofacetylcholinesterase inhibitors, such as rivastigmine. In certainembodiments, the present invention may provide a reduced incidence ofside effects, when compared with current treatments and/or deliverymethods.

Preferably the person is in need of such treatment, although thecompound may be administered in a prophylactic sense.

References to a “neurodegenerative condition”, a “neurodegenerativedisorder” or a “neurodegenerative disease”, are used interchangeably,and should be understood as a reference to a condition characterised byneurologically based cognitive, emotional and behavioural disturbances.

Neurodegenerative conditions may affect brain or peripheral nervefunction. They result from the deterioration of neurons and they arecharacterised by progressive central or peripheral nervous dysfunction.They are divided into two groups: conditions causing problems withmovement or sensation and conditions affecting memory or related todementia. In one or more embodiments, the neurodegenerative condition isa condition which is associated with modulation of acetylcholinesterase.For example, neurodegenerative conditions in accordance with theinvention may include Alzheimer's disease, Alexander disease, Alper'sdisease, amyotrophic lateral sclerosis, ataxia, telangiectasia, Canavandisease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakobdisease, dementia, Huntington disease, Kennedy's disease, Krabbedisease, Lewy body dementia, Machado-Joseph disease, multiple sclerosis,Parkinson's disease, Pelizaeus-Merzbacher disease, Fronto-TemporalDementia, Pick's disease, primary lateral sclerosis, Refsum's disease,Sandhoff disease, Schilder's disease, Steele-Richardson-Olszewskidisease, tabes dorsalis, Guillain-Barre Syndrome and peripheralneuropathies such as traumatic (nerve severing or crushing), ischemic,metabolic (diabetes, uraemia), infectious, alcoholic, iatrogenic, andgenetic neuropathies.

The term “dementia”, as used herein would be clear to persons skilled inthe art and includes conditions characterised by neurologically-basedcognitive, emotional and behavioural impairment, in particular theDiagnostic and Statistical Manual of Mental Disorders IV outlinescharacterises dementia by the presence of:

-   -   Multiple cognitive deficits, including memory impairment and at        least one of the following: aphasia, apraxia, agnosia or        disturbance in executive functioning; and    -   Impairment of social or occupational function

Reference to “characteristic symptoms of dementia” and “characteristicsymptoms of Alzheimer's disease” should be understood as a reference toany one or more symptoms which may occur in an individual suffering fromdementia, in particular dementia associated with disease such asAlzheimer's disease or Parkinson's disease. These symptoms may beevident throughout the disease course or they may be evident onlytransiently or periodically. For example, an individual may exhibitsevere memory impairment impaired social function in response tospecific environmental cues or stressors. It should also be understoodthat the subject symptoms may not necessarily be exhibited by allindividuals suffering from dementia or Alzheimer's disease. For example,some individuals may suffer from cognitive deficits without obviousimpairment of social function. However, for the purpose of the presentinvention, any such symptoms, irrespective of how many or few patientsever actually exhibit the given symptom, are encompassed by thisdefinition. Without limiting the present invention to any one theory ormode of action, the symptoms that are most commonly associated withAlzheimer's disease include cognitive deficits and impaired social oroccupational function.

Examples of cognitive deficits and impaired social or occupationalfunction include, but are not limited to:

-   -   Forgetfulness, especially of the names of family members,        everyday objects appointments or events;    -   Misplacing items or possessions;    -   Disorientation and misinterpreting spatial relationships;    -   Impairment of speech and writing;    -   Difficulty thinking, concentrating or and reasoning;    -   Difficulty making routine judgments and decisions;    -   Difficulty planning and performing familiar tasks; and    -   Changes in personality and behaviour; including depression,        anxiety, social withdrawal, mood swings, distrust, irritability        and aggressiveness, changes in sleeping habits, wandering, loss        of inhibitions and delusions

In addition to the fact that there may be significant variation betweendementia and/or Alzheimer's patients in terms of the symptoms theyexhibit, it should also be understood that there are other conditionsand disorders which are also characterised by one or more of thesesymptoms. For example similar dementia symptoms, are also commonlyobserved in patients with Parkinson's disease. Accordingly, reference toa condition characterised by one or more symptoms characteristic ofdementia and/or Alzheimer's disease should be understood as a referenceto any neurodegenerative condition which is characterised by thepresence of one or more of these symptoms.

In one embodiment, said condition is a condition characterised by one ormore symptoms of dementia.

In another embodiment, said condition is Alzheimer's disease.

The term “mammal” as used herein includes humans, primates, livestockanimals (e.g. horses, cattle, sheep, pigs, donkeys), laboratory testanimals (e.g. mice, rats, guinea pigs), companion animals (e.g. dogs,cats) and captive wild animals (e.g. kangaroos, deer, foxes).Preferably, the mammal is a human.

For certain of the abovementioned conditions it is clear that themethods of the invention may be used prophylactically as well as for thealleviation of acute symptoms. References herein to “treatment” or thelike may therefore include such prophylactic treatment, as well astherapeutic treatment of acute conditions or symptoms. Accordingly, Inone or more embodiments, the present invention provides intranasalcompositions for therapeutic treatment of neurodegenerative diseases ordisorders. In other embodiments, the present invention providesintranasal compositions for prophylactic treatment of neurodegenerativediseases or disorders.

One of skill in the art will be familiar with the difficulties inadministering traditional medications, including lag phases before theeffects are observed, and/or systemic dosage concentration peaks andtroughs following administration.

The present invention relates to an intranasal composition comprising anacetylcholinesterase inhibitor that may provide sustained, enhanceddelivery of the active agent across nasal mucosa over a prolongedperiod. In particular, intranasal delivery across nasal mucosa inaccordance with the invention may advantageously provide sustained,enhanced systemic delivery of rivastigmine and its primary metabolite,3-[(1S)-1-(dimethylamino)ethyl]phenol, also referred to as NAP 226-90(hereafter “NAP 226-90” or “the primary metabolite of rivastigmine”).

Accordingly, in one aspect the present invention provides a compositionfor intranasal delivery comprising an acetylcholinesterase inhibitor. Inparticular, the composition according to the present invention may beadministered for treatment or prevention of neurodegenerative diseasesor disorders, such as dementia associated with Alzheimer's disease.Specifically, in one or more embodiments, the present invention providesa composition comprising rivastigmine or a pharmaceutically acceptablesalt thereof for intranasal delivery.

It is estimated that the potency of NAP 226-90 is 10 times less thanrivastigmine (Gobburu et al. 2001). Kurz et al. (2009) indicated thatoral administration of rivastigmine may result in a NAP 226-90 torivastigmine plasma ratio greater than one. Furthermore, in the case oforal administration of rivastigmine, higher plasma ratios of NAP 226-90to rivastigmine have been linked to greater and undesirable levels ofperipheral anticholinesterase inhibition. As previously described,peripheral cholinesterase inhibition has been associated with increasedincidence of adverse events and/or unwanted side effects, such asnausea, vomiting and diarrhoea. Without wishing to be bound by theory,presystemic metabolism due to direct exposure of rivastigmine to the gutwall or by hepatic first-pass metabolism of rivastigmine may beresponsible for higher plasma ratios of the metabolite NAP 226-90 torivastigmine in the case of oral administration. Accordingly, lowerplasma ratios of the metabolite NAP 226-90 to rivastigmine are thusdesirable.

The intranasal administration of an aqueous solution comprisingrivastigmine in accordance with the invention may provide a lower plasmaratio of the metabolite NAP 226-90 to rivastigmine when compared withoral dosing of rivastigmine. In one or more embodiments, intranasaladministration in accordance with the present invention mayadvantageously provide a plasma ratio of NAP 226-90 to rivastigmine ofless than about 1.4:1, preferably less than about 1.2:1, more preferablyless than about 1:1, still more preferably less than about 0.8:1, mostpreferably less than about 0.6:1.

It is understood that the active agents in accordance with the presentinvention may be provided as the free base form or as a pharmaceuticallysalt or derivative. The term “pharmaceutically acceptable salts”includes pharmaceutically acceptable solvates and hydrates, andpharmaceutically acceptable addition salts of the compounds.

Pharmaceutically acceptable derivatives of rivastigmine could beprovided in the form of a prodrug, which may, upon administration to asubject, be capable of providing (directly or indirectly) a compound ofthe present invention or an active metabolite or residue thereof.

In one or more embodiments, the pharmaceutically acceptable salts inaccordance with the invention may include acid addition salts, and thesalts of quaternary amines and pyridiniums. For use in medicine, thesalts of the provided compounds will be pharmaceutically acceptablesalts, but it will be appreciated that non-pharmaceutically acceptablesalts also fall within the scope of the present invention, since theseare useful as intermediates in the preparation of pharmaceuticallyacceptable salts. A pharmaceutically acceptable salt involves theinclusion of another molecule such as an acetate ion, a succinate ion, atartrate ion or other counter ion. The counter ion may be any organic orinorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. When multiple charged atoms are presentin the parent drug, its pharmaceutically acceptable salts will havemultiple counter ions and these can be several instances of the samecounter ion or different counter ions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms in the parentcompound and/or one or more counter ions.

Acid addition salts are formed from a compound of the invention and apharmaceutically acceptable inorganic or organic acid including but notlimited to hydrochloric, hydrobromic, sulfuric, phosphoric,methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic,ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic,or tartaric acids. The counter ion of quaternary amines and pyridiniumsinclude chloride, bromide, iodide, sulfate, phosphate, methansulfonate,citrate, acetate, malonate, fumarate, sulfamate, and tartrate. Also,basic nitrogen-containing groups may be quaternised with such agents aslower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl and diethylsulfate; and others. The preparation of the pharmaceutically acceptablesalts described above and other typical pharmaceutically acceptablesalts is more fully described by Berge et al., “Pharmaceutical Salts,”J. Pharm. Sci., 1977:66:1-19.

In some embodiments, salts of the active agents in accordance with theinvention may be prepared from the free form of the compound in aseparate synthetic step prior to incorporation into the compositions ofthe present invention. In still other embodiments, salts of the activeagents in accordance with the invention may be prepared in situ duringpreparation of the composition for administration. For example, thecomposition for administration may further comprise an appropriate acidwhich, upon contact with the free form of the active agent, forms adesired pharmaceutical salt in situ for administration.

In one or more embodiments, the compositions for intranasal deliverycomprise an acetylcholinesterase inhibitor such as rivastigmine or apharmaceutically acceptable salt thereof. Where rivastigmine is providedas a pharmaceutically acceptable salt, it may be provided as an acidaddition salt. Acid addition salts of rivastigmine in accordance withthe invention include hydrochloric, hydrobromic, sulfuric, phosphoric,methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic,ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic,or tartaric acid salts. In particular, rivastigmine in accordance withthe invention may be provided as a tartrate salt. In some embodiments, arivastigmine salt may be prepared from the free form of the compoundprior to incorporation into the compositions of the present invention.In still other embodiments, the desired rivastigmine salt may be formedby addition of an appropriate acid to the free form of the compound insitu prior to administration.

As previously described, the present invention encompasses intranasalcompositions comprising a desired active agent as the free base form oras a pharmaceutically salt or solvate thereof. Where specific dosages orconcentrations of, for example, rivastigmine are referred to herein, itis understood that the specific dosage or concentration refers to theconcentration of or equivalent to the free base of rivastigmine.Accordingly, where a pharmaceutically acceptable salt of an active agentis used, for example rivastigmine tartrate, a person skilled in the artwould readily understand that the concentrations or dosages in respectof the salt, refers to the equivalent concentration or dosage of thefree base form of rivastigmine. In some embodiments, the intranasalpharmaceutical composition comprises an aqueous formulation ofrivastigmine or a pharmaceutically acceptable salt wherein therivastigmine in an amount of about 0.05 to about 20% w/v, about 0.10 toabout 15% w/v, about 0.15 to about 6% w/v, about 0.2 to about 5% w/v,about 0.3 to about 3% w/v, about 0.6 to about 2.5% w/v, about 1 to about2% w/v; about 1.25 to about 1.75% w/v. In still other embodiments, theintranasal pharmaceutical composition comprises an aqueous formulationof rivastigmine or a pharmaceutically acceptable salt wherein therivastigmine in an amount of about 0.5% to about 15% by weight.

It has surprisingly been found that the specific combination ofrivastigmine or a pharmaceutically acceptable salt thereof, a pHmodifying agent and a thickening agent in accordance with the inventionmay advantageously balance the ease of administration by intranasaldelivery with the subsequent adherence to the nasal mucosa. Inparticular, the aqueous formulations comprising rivastigmine, a pHmodifying agent and a thickening agent in accordance with the inventionmay offer improved balance between viscosity, sprayability, absorption,sustained release and/or enhanced bioavailability for effectiveintranasal administration of active agents. In particular, the specificcombination of agents may offer improved trans-nasal absorption andincreased residence time on the nasal mucosa to ultimately provideenhanced bioavailability and/or sustained release of the desired activeagent without adversely affecting the ease of administration, inparticular as an intranasal spray. Furthermore, the judicious selectionof agents and components may enable low or reduced doses of an active tobe administered, longer duration of action, and/or a reduced incidenceof side effects when compared with other drug delivery methods. Forexample, the specific combination of agents of the formulationscomprising rivastigmine in accordance with the invention mayadvantageously provide a formulation which balances viscosity,sprayability and absorption such that it may be administeredintranasally. Furthermore, the specific combination of agents inaccordance with the present invention, which provides a formulation thatmay be administered intranasally, may also advantageously provideimproved methods of treating neurodegenerative diseases in a mammal,such as Alzheimer's disease or Parkinson's disease.

The pH modifying agent used in the intranasal formulation of the presentinvention may be any pharmaceutically acceptable pH-modifying agentwhich provides or adjusts the pH of the formulation to a pH in the rangeof about 3 to 6. Where the intranasal formulations of the presentinvention are formulated with a pH in the range of about 3 to 6, theformulation, in particular the active agent, may advantageously exhibitincreased pharmaceutical stability and/or shelf life. For example, ithas surprisingly been found that rivastigmine tartrate formulated in anaqueous intranasal spray solution with pH range of about 3 to 6 inaccordance with the invention, is pharmaceutically stable over aprolonged time period, such as at least 3 months, preferably at least 6months, more preferably at least 1 year, even more preferably at least 2years. Furthermore, formulating intranasal formulations with a pH in therange of about 3 to 6 in accordance with the invention mayadvantageously assist in solubilising the active agent in solution.Accordingly, the pH modifying agent may be any agent suitable for useand administration in an intranasal formulation which provides oradjusts the pH of the formulation to a pH in the range of about 3 to 6.In one or more embodiments, the pH modifying agent in accordance withthe invention may be a buffer. In one or more other embodiments, the pHmodifying agent may be any pharmaceutically acceptable acidifying oralkalizing agent that is compatible with the other components of thecompositions and which adjusts the pH of the formulation to a pH in therange of about 3 to 6. Suitable pH modifying agents in accordance withthe invention include but are not limited to organic acids and theircorresponding salts, mineral acids, alkali metal phosphates, carbonates,borates, hydroxides, base and mixtures thereof. In one or moreembodiments, the pH modifying agent is selected from lactic acid, citricacid, tartaric acid, phosphoric acid, acetic acid, hydrochloric acid,nitric acid and their corresponding salts, sodium or potassiummetaphosphate, sodium or potassium phosphate, sodium or potassiumacetate, ammonia, sodium carbonate, sodium or potassium hydroxide,dibasic sodium phosphate, sodium borate, and mixtures thereof. In one ormore other embodiments, the pH modifying agent may be a buffer. Inparticular, a buffer in accordance with the invention may comprise anacid and a salt, such as the corresponding salt of the acid. Suitablebuffers include, but are not limited to, citrate, phosphate, acetate andglycinate buffers, wherein the buffer adjusts or maintains the pH of theformulation to a pH in the range of about 3 to 6.

As described above, the pH modifying agent in accordance with theinvention may be any agent which provides or adjusts the pH of theformulation to a pH in the range of about 3 to about 6, preferably inthe range of about 3 to 5, more preferably about 3 to 4. In otherembodiments, the pH modifying agent in accordance with the invention isan agent which provides or adjusts the pH of the formulation to a pH ofabout 3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 4,about 4.5, about 5, about 5.5, or about 6. In one or more embodiments,the pH modifying agent is a citrate buffer. In some embodiments, thecitrate buffer may comprise citric acid and a citrate salt, such assodium citrate. In particular, the buffer may comprise from about 0.01%to about 1% by weight of the total composition. In still otherembodiments, the pH modifying agent is an organic acid alone, such ascitric acid.

The intranasal formulations of the present invention may also comprise athickening agent. The use of a thickening agent may provide improvedadherence of the formulation to the nasal mucosa without adverselyaffecting the ease of administration, in particular administration as anintranasal spray. Furthermore, the thickening agent may advantageouslyimprove the trans-nasal absorption of the active agent, increase theresidence time of the formulation on the nasal mucosa and/or reduce lossof the formulation via mucociliary clearance of the nasal passages. Assuch, the use of a thickening agent may advantageously provide enhancedbioavailability and/or sustained release of the desired active agent.

In one or more embodiments, the thickening agent in accordance with theinvention may be any pharmaceutically acceptable, nasal mucosa-tolerantexcipient known to those skilled in the art. The thickening agent inaccordance with the invention may advantageously contribute to thecontrolled release of the active ingredient on the mucosal membranes.Suitable thickening agents in accordance with the invention includemethylcellulose, ethylcellulose, hydroxy-ethylcellulose, hydroxyl propylcellulose, hydroxy propyl methylcellulose, sodium carboxymethylcellulose; polyacrylic acid polymers, poly hydroxyethylmethylacrylate; polyethylene oxide; polyvinyl pyrrolidone; polyvinylalcohol, tragacanth, sodium alginate, araya gum, guar gum, xanthan gum.lectin, soluble starch, gelatin, pectin and chitosan. In particular, thethickening agent may be polyvinyl pyrrolidone, also referred to as USPpovidone or PVP.

In one or more embodiments, the formulations of the present inventionmay comprise an amount of a thickening agent which improves adherence ofthe formulation to the nasal mucosa without adversely affectingadministration of the formulation as an intranasal spray. Specifically,in one or more embodiments the thickening agent may comprise about 0.1%to about 2% by weight of the total composition, preferably thethickening agent may comprise about 0.25% to about 1.5% by weight of thetotal composition, more preferably the thickening agent may compriseabout 0.5% to about 1% by weight of the total composition.

In one or more embodiments, the intranasal compositions in accordancewith the invention may further comprise a sensory agent. The inclusionof a sensory agent may provide the patient with sensory feedback uponuse, which allows the patient to recognize that administration hasoccurred, and may aid the patient's recollection of administration. Forexample, a sensory agent may provide direct feedback to the patient thatthe dose has been delivered to the correct location within the nasalpassages. In particular, in some aspects the sensory agent may providemucosal feel, pleasant aroma (smell) and an appealing taste. Forexample, when a sensory agent is delivered in an intranasal formulation,a small amount of residual formulation may be removed by mucociliaryclearance of the nasal passages towards the nasopharynx and eventuallyswallowed to provide a pleasant taste. The inclusion of a sensory agentmay also advantageously provide improved patient compliance and/or apositive psychological effect. Furthermore, in view of the fact that thesensory agent may provide direct feedback to the patient that the dosehas been delivered, it advantageously eliminates the need for an‘audible click’ within the metered-dose nasal spray device as a means ofregistering to the patient that a dose has been delivered. For example,a marketed fentanyl intranasal spray for the treatment of break-throughpain relies on an audible click device to provide feedback to patients.Simplifying the metered-dose nasal spray device, for example byeliminating the need for an ‘audible click’, also has the benefit ofreducing the cost of manufacture of the nasal spray of this invention asa standard metered-dose nasal spray nozzle, actuator and bottle can beused if desired.

The inclusion of a sensory agent may also enhance the prophylactic ortherapeutic effect of compositions of the present invention. Forexample, the inclusion of a sensory agent may improve the delivery ofrivastigmine across the nasal mucosa, assist partitioning into the mucuslayer and nasal mucosa to aid absorption and/or aid in the break-up ofthe spray plume upon actuation of a metered-dose nasal spray nozzle,that is, by increasing and/or maintaining the desired spray plume angleupon actuation. Furthermore, the sensory agent may also adjust theviscosity in combination with the thickening agent, to further balancethe ease of administration of the formulation, in particular as anintranasal spray, with the subsequent adherence of the formulation tothe nasal mucosa.

In one or more embodiments, the sensory agent in accordance with theinvention may be any pharmaceutically acceptable, nasal mucosa-tolerantexcipient known to those skilled in the art. In some embodiments, thesensory agent may be selected from coolants, salivating agents, andwarming agents. Suitable sensory agents include, but are not limited to,a C2 to C4 alcohol, such as ethanol or isopropanol, menthols, terpenes,thymol, camphor, capsicum, phenol, carveol, menthol glucuronide,eucalyptus oil, benzyl alcohol, salicyl alcohol, clove bud oil, mint,spearmint, peppermint, eucalyptus, lavender, citrus, lemon, lime,hexylresorcinol, ketals, diols, and mixtures thereof. Other suitablemucosa-tolerant terpenes are described in Williams and Barry (2001),incorporated herein by reference.

In one or more embodiments, the aqueous intranasal formulations inaccordance with the invention may advantageously provide an absolutebioavailability equivalent to at least 60% of the active agent, forexample, rivastigmine free base. The terms “bioavailability” or“bioavailable” as used herein refer generally to the rate and extent ofabsorption of a given active agent into the systemic circulation and,more specifically, the rate or measurements intended to reflect the rateand extent to which a given active agent becomes available at the siteof action or is absorbed from a drug product and becomes available atthe site of action. For example, the extent and rate of absorption of agiven active agent from a composition for nasal administration of thepresent invention may be reflected by a time-concentration curve of saidactive agent in systemic circulation. For measurement and calculationpurposes bioavailability means the fraction of the administered dose ofthe active agent that reaches the systemic circulation (i.e. bloodstream). It can range from 0% (no active agent) to 100% (all theadministered active agent). Absolute bioavailability is the amount ofactive agent from a formulation that reaches the systemic circulationrelative to an intravenous (IV) dose. The IV dose is assumed to be 100%bioavailable since the active agent is injected directly into thesystemic circulation. Absolute bioavailability (F) can be calculated bydividing the AUC_(0-∞) nasal by the AUC_(0-∞). IV, where AUC_(0-∞) isthe area under the curve of the blood plasma concentration-time profileof the active agent from zero to infinity hours for an equivalent nasaland IV dose, respectively. Accordingly, in one or more embodiments, theaqueous intranasal formulations in accordance with the invention mayadvantageously provide an absolute bioavailability equivalent to atleast 60% of the active agent, preferably an absolute bioavailabilityequivalent to at least 65% of the active agent, more preferably anabsolute bioavailability equivalent to at least 70% of the active agent,even more preferably an absolute bioavailability equivalent to at least75% of the active agent, even more preferably an absolutebioavailability equivalent to at least 80% of the active agent, mostpreferably an absolute bioavailability equivalent to at least 85% of theactive agent. Without wishing to be bound by theory, a person skilled inthe art would recognise that a degree of variability may exist in theabsolute bioavailability of a given drug when administered as an aqueousintranasal formulation in accordance with the invention betweenindividual patients depending on factors including, for example, generalhealth, intrinsic drug clearance rates and the nature of the drugadministered. Accordingly, in some embodiments, the intranasalformulations in accordance with the invention may advantageously provideimproved individual dosage adjustment within, below and above aneffective dosing range, particularly where a degree in variability inbioavailability is observed or required. For example, it is recognisedthat the intrinsic clearance (CL) of rivastigmine varies up to 4-fold inAlzheimer's disease patients (Hossain et al. 2002). Accordingly, theintranasal formulations described herein advantageously enable flexibleindividual dosage adjustment as required.

Furthermore, in one or more embodiments the aqueous intranasalformulations in accordance with the invention may advantageously providean improved dose response, that is, for example with regard to thedegree of absorption, the rate of absorption, and/or the duration ofaction or efficacy. Bioequivalence as used herein is understood to meanthat an active agent in two or more alternative dosage forms reach thegeneral circulation at the same relative rate and the same relativeextent, that is, the plasma or serum level profile of a given activeobtained by administration of the two alternative dosage forms aresubstantially similar. Furthermore, a person skilled in the art wouldrecognise that the relative rate and degree of absorption of a givenactive may be characterised by a range of measures, including forexample, the maximum plasma concentration (C_(max)), time to maximumplasma concentration (T_(max)), therapeutic plasma concentration(C_(ther)), average plasma concentration (C_(avg)) and/or the length oftime therapeutic plasma concentration is maintained (T_(maint))following administration of a given dose.

In one or more embodiments the aqueous intranasal formulations inaccordance with the present invention may provide a maximum therapeuticrivastigmine plasma concentration (C_(max)) of at least about 3000pg/mL, preferably about 4000 pg/mL. more preferably about 5000 pg/mL.Additionally, in one or more further embodiments, the time to maximumrivastigmine plasma concentration (T_(max)) is less than 3 hours, morepreferably less than 2 hours, even more preferably less than 1.5 hours,even more preferably less than 1.25 hours following administration of aninitial dose at time equals zero hours. Furthermore, in one or moreother embodiments, the aqueous intranasal formulations in accordancewith the present invention may provide a therapeutic rivastigmine plasmaconcentration (C_(ther)) in the range of about 2000 pg/mL to about20,000 pg/mL, preferably about 2500 pg/mL to about 15,000 pg/mL, morepreferably about 3500 pg/mL to about 10,000 pg/mL, even more preferablyabout 4000 pg/mL to about 8,000 pg/mL. In one or more other embodiments,the aqueous intranasal formulations in accordance with the presentinvention may provide an average plasma concentration (C_(avg)) in therange of about 500 pg/mL to about 20,000 pg/mL, where C_(avg) iscalculated from the AUC over a given time interval (AUC_(0-6 h)) dividedby the prospective dosage interval. Additionally, in one or more furtherembodiments, the therapeutic rivastigmine plasma concentration(C_(ther)) in the range of about 2000 pg/mL to about 20,000 pg/mL may bemaintained (T_(maint)) for a period of at least 4 hours, preferably atleast 4.5 hours, more preferably at least 5 hours, even more preferablyat least 5.5 hours, even more preferably 6 hours followingadministration of an initial dose at time equals zero hours. It would beunderstood by a person skilled in the art that the therapeuticrivastigmine plasma concentration (C_(ther)) could be maintained(T_(maint)) for an even longer period, for example at least 8 hours,preferably at least 10 hours, more preferably at least 12 hours where arepeat dose is subsequently administered. For example, a therapeuticrivastigmine plasma concentration (C_(ther)) could be maintained(T_(maint)) for a period of 12 hours where a repeat dose is administeredat least 4 hours, preferably at least 4.5 hours, more preferably atleast 5 hours, even more preferably at least 5.5 hours, even morepreferably 6 hours after the first dose is administered. In stillfurther embodiments, the therapeutic rivastigmine plasma concentration(C_(ther)) in the range of about 2000 pg/mL to about 20,000 pg/mL may bemaintained (T_(maint)) for waking hours. Advantageously, an intranasalformulation having a C_(max), a C_(avg), a C_(ther), a T_(max) and/or aT_(maint) as described may alleviate or treat one or more of thesymptoms associated with a given neurodegenerative disorder, such asAlzheimer's disease. In still other embodiments, a C_(max), a C_(avg), aC_(ther), a T_(max), and/or a T_(maint) as described may provide asustained-release treatment for a given neurodegenerative disorder, suchas Alzheimer's disease. In one or more embodiments, the absolutebioavailability (F) and T_(maint) may advantageously be maximised whilstminimising the C_(max) to C_(ther) ratio.

In some embodiments, the intranasal compositions in accordance with thepresent invention may further comprise an antioxidant, surfactant,co-solvent, adhesive, stabilizer, osmolarity adjusting agent,preservative, penetration enhancer, chelating agent, sweetening agent,flavoring agent, taste masking agent, or colorant. Furthermore, someagents or components of the intranasal formulations in accordance withthe invention may concurrently act, for example, as both a pH modifyingagent and an osmolarity adjusting agent or as both sensory agent and aco-solvent. For example, where ethanol is used as a sensory agent inaccordance with the invention, it may further function as a penetrationenhancer and/or a cosolvent. Where a given agent or component of anintranasal formulation is described herein with respect to a particularfunction, it is in no way taken to be limited to a single function only.It would be understood by a person skilled in the art that agents orcomponents may additionally perform alternative or multiple functions.

Where the intranasal compositions in accordance with the inventioncomprise a co-solvent, the co-solvent may be any pharmaceuticallyacceptable co-solvent. Co-solvents in accordance with the presentinvention may include but are not limited to alcohols, polyvinylalcohols, propylene glycol, polyethylene glycols and derivativesthereof, glycerol, sorbitol, polysorbates, ethanol, and mixturesthereof. In particular, the co-solvent in accordance with the presentinvention is selected from glycerol, propylene glycol and mixturesthereof. In still other embodiments, the co-solvent may comprise fromabout 1% to about 60% by volume of the total composition, preferablyfrom about 2 to about 50%, more preferably from about 3 to about 40%,even more preferably from about 5 to about 35% by volume of the totalcomposition. In some embodiments, the sensory agent in accordance withthe invention may, for example, additionally act as a co-solvent or apenetration enhancer.

Where the intranasal compositions in accordance with the inventioncomprise a preservative, the preservative may be selected from anypharmaceutically acceptable preservative. In one or more embodiments,the preservative may be selected from benzalkonium chloride,methylparaben, ethylparaben, propylparaben, butylparaben, benzylalcohol, sodium benzoate, phenylethyl alcohol, and benzethonium. Moreparticularly, the preservative may include benzyl alcohol or sodiumbenzoate. In one or more embodiments, the preservative may comprise fromabout 0.1% to about 5% by weight of the total composition, preferablyfrom about 0.2 to about 3% by weight, more preferably from about 0.3% toabout 1% by weight of the total composition. In still other embodiments,the intranasal compositions in accordance with the invention do notcontain a preservative.

In certain embodiments, it is envisaged that the intranasal compositionscomprising rivastigmine described herein may be administered to a personin need thereof as a substitute or replacement for other traditionalmedication. In other embodiments, it is envisaged that intranasalcompositions comprising rivastigmine in accordance with the inventionmay be administered to a subject in need thereof as a supplement oradjunct to traditional medication. In still other embodiments, it isenvisaged that intranasal compositions comprising rivastigmine inaccordance with the invention may be administered to a person in needthereof in the absence of adjunct therapy. In still other embodiments,it is envisaged that that intranasal compositions comprisingrivastigmine in accordance with the invention may be administered to aperson in need thereof in conjunction with, or as an adjunct to,behavioural or cognitive therapies.

Replacing traditional medication with an intranasal compositioncomprising rivastigmine in accordance with the invention may beadvantageous, particularly where the traditional medication isassociated with one or more adverse effects (for example, nausea,vomiting, diarrhoea). Examples of medication would be known to thoseskilled in the art and include, but are not limited to, orally availablesystemic medications comprising rivastigmine and transdermal patchescomprising rivastigmine.

In other embodiments, the intranasal compositions comprisingrivastigmine in accordance with the invention may be administered to asubject in need thereof, together with other medication for a discreteperiod of time, to address specific symptoms. In still otherembodiments, the person in need thereof may be treated with both anintranasal composition comprising rivastigmine and one or moreadditional medications (administered sequentially or in combination) forthe duration of the treatment period. Such combination therapy may beparticularly useful, for example, where an additive or synergistictherapeutic effect is desired.

“Treat”, “treating” or “treatment” with regard to a disorder or diseaserefers to alleviating or abrogating the cause and/or the effects of thedisorder or disease. As used herein, the terms “treat”, “treatment” and“treating” refer to the reduction or amelioration of the progression,severity and/or duration of condition, or the amelioration of one ormore symptoms (e.g., one or more discernable symptoms) of said condition(i.e., “managing” without “curing” the condition), resulting from theadministration of one or more therapies (e.g., one or more therapeuticagents such as a compound or composition of the invention). In specificembodiments, the terms “treat”; “treatment” and “treating” refer to theamelioration of at least one measurable physical parameter of acondition described herein. In other embodiments the terms “treat”,“treatment” and “treating” refer to the inhibition of the progression ofa condition described herein, either physically by, e.g., stabilizationof a discernable symptom or physiologically by, e.g., stabilization of aphysical parameter, or both.

The terms “preventing” and “prophylaxis” as used herein refer toadministering a medicament beforehand to avert or forestall theappearance of one or more symptoms of a disease or disorder. The personof ordinary skill in the medical art recognizes that the term “prevent”is not an absolute term. In the medical art it is understood to refer tothe prophylactic administration of a drug to substantially diminish thelikelihood or seriousness of a condition, or symptom of the conditionand this is the sense intended in this disclosure. As used in a standardtext in the field, the Physician's Desk Reference, the terms “prevent”,“preventing” and “prevention” with regard to a disorder or disease,refer to averting the cause, effects, symptoms or progression of adisease or disorder prior to the disease or disorder fully manifestingitself.

The terms “therapeutic equivalence” or “therapeutically equivalent” asused herein refer to compositions for nasal administration which willproduce the same clinical effect and safety profile and/or arepharmaceutical equivalents to other systemic treatments such as orallyavailable compositions. For example, a therapeutic equivalent intranasalcomposition comprising rivastigmine may provide substantially the sameefficacy and toxicity at a lower dosage strength than other systemictreatments such as orally available compositions.

The intranasal compositions of the present invention are administered tothe person in need thereof in a treatment effective amount. In someembodiments, a treatment effective amount is a therapeutically effectiveamount or a prophylactically effective amount. The term “therapeuticallyeffective amount” as used herein means that amount of an activecompound, such as an acetylcholinesterase inhibitor includingrivastigmine, or pharmaceutical agent sufficient to treat or alleviatethe symptoms associated with a given neurodegenerative disorder, such asdementia caused by Alzheimer's disease. The therapeutically effectiveamount of the compound to be administered will be governed by suchconsiderations, and is either, an incremental maximum tolerated dose, orthe minimum amount, necessary to ameliorate, cure, or treat the diseaseor disorder or one or more of its symptoms. The term “prophylacticallyeffective amount” refers to an amount effective in preventing orsubstantially lessening the chances of acquiring a disease or disorderor in reducing the severity of the disease or disorder before it isacquired or reducing the severity of one or more of its symptoms beforethe symptoms develop. Roughly, prophylactic measures are divided betweenprimary prophylaxis (to prevent the development of a disease or symptom)and secondary prophylaxis (whereby the disease or symptom has alreadydeveloped and the patient is protected against worsening of thisprocess).

As used herein, the term “effective amount” relates to an amount ofcompound which, when administered according to a desired dosing regimen,provides the desired therapeutic activity. Suitable dosages lie withinthe range of about 0.1 ng per kg of body weight to 100 g per kg of bodyweight per dosage. The dosage may be in the range of 1 μg to 10 g per kgof body weight per dosage, such as is in the range of 1 mg to 1000 mgper kg of body weight per dosage. In one embodiment, the dosage may bein the range of 1 mg to 500 mg per kg of body weight per dosage. Inanother embodiment, the dosage may be in the range of 1 mg to 250 mg perkg of body weight per dosage. In yet another embodiment, the dosage maybe in the range of 1 mg to 200 mg per kg of body weight per dosage, suchas up to 50 mg per kg body weight per dosage.

Dosing may occur at intervals of minutes, hours, days, weeks, months oryears or continuously over any one of these periods. Suitable dosageintervals include 24 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3hours, 2 hours, 1 hour, 30 minutes, or 15 minutes. In particular, theintranasal compositions according to the present invention may beadministered at an interval of 12 hours, 8 hours, 6 hours or four hours.In still other embodiments, dosing may occur during waking hours orsleeping hours only. Where dosing occurs in waking hours, for example,the administered amount may be an amount sufficient to treat oralleviate the symptoms associated with a given neurodegenerativedisorder, such as dementia caused by Alzheimer's disease. Where theactive agent is associated with one or more side effects, dosing mayoccur at intervals sufficient to treat or alleviate the symptoms of agiven disease or disorder and concurrently minimise or reduce theassociated side effects. In one or more embodiments, where the activeagent to be administered is rivastigmine or a pharmaceuticallyacceptable salt thereof for the treatment of dementia caused byAlzheimer's disease, dosing may advantageously occur during waking hoursonly to reduce side effects such as disrupted sleep patterns. Disruptedsleep patterns have been associated with administration of existingrivastigmine transdermal patches for a continuous period of 24 hourswhich necessarily includes sleeping hours. In one or more embodiments,intranasal formulations in accordance with the present invention mayprovide adjustable, individualised dosing, in particular dosing duringwaking hours, which may advantageously minimise undesirable cholinergicburden and sleep disturbances whilst delivering an effective dose forthe treatment of dementia associated with Alzheimer's and Parkinson'sdisease.

The terms “administer”, “administering” or “administration” in referenceto a compound, composition or formulation of the invention meansintroducing active agent into the system of the animal in need oftreatment. When the active agent in accordance with the invention isprovided in combination with one or more other active agents,“administration” and its variants are each understood to includeconcurrent and/or sequential introduction of the compound and the otheractive agents.

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 3000mg, about 0.0001 mg to about 200 mg, about 0.001 mg to about 1500 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of an extract or compound perunit dosage form.

In certain embodiments, the intranasal compositions of the invention maybe at dosage levels sufficient to deliver from about 0.001 mg/kg toabout 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, fromabout 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10mg/kg, and from about 1 mg/kg to about 25 mg/kg, of subject body weightper day, one or more times a day, to obtain the desired therapeuticeffect.

Suitable dosage amounts and dosing regimens can be determined by theattending physician and may depend on the particular condition beingtreated, the severity of the condition as well as the general age,health and weight of the subject. It will be appreciated that doseranges as described herein provide guidance for the administration ofprovided pharmaceutical compositions to an adult. The amount to beadministered to can be determined by a medical practitioner or personskilled in the art.

The intranasal compositions of the present invention may be used incombination therapy with one or more additional therapeutic agents. Forcombination treatment with more than one active agent, where the activeagents are in separate dosage formulations, the active agents may beadministered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

When co-administered with other agent, an “effective amount” of thesecond agent will depend on the type of drug used. Suitable dosages areknown for approved agents and can be adjusted by a person skilled in theart according to the condition of the subject, the type of condition(s)being treated and the amount of a compound, extract or composition beingused. In cases where no amount is expressly noted, an effective amountshould be assumed. For example, compounds described herein can beadministered to a subject in a dosage range from between about 0.01 toabout 10,000 mg/kg body weight/day, about 0.01 to about 5000 mg/kg bodyweight/day, about 0.01 to about 3000 mg/kg body weight/day, about 0.01to about 1000 mg/kg body weight/day, about 0.01 to about 500 mg/kg bodyweight/day, about 0.01 to about 300 mg/kg body weight/day, about 0.01 toabout 100 mg/kg body weight/day.

The phrase “combination therapy” as used herein, is understood to referto administration of an effective amount, using a first amount of forexample rivastigmine or a pharmaceutically acceptable salt thereof asdescribed herein, and a second amount of an additional suitabletherapeutic agent.

In certain embodiments, rivastigmine or a pharmaceutically acceptablesalt thereof, and the additional therapeutic agent, are eachadministered in an effective amount (i.e., each in an amount which wouldbe therapeutically effective if administered alone). In otherembodiments, rivastigmine or a pharmaceutically acceptable salt thereof,and the additional therapeutic agent are each administered in an amountwhich alone does not provide a therapeutic effect (a sub-therapeuticdose). In yet other embodiments, rivastigmine or a pharmaceuticallyacceptable salt thereof, can be administered in an effective amount,while the additional therapeutic agent is administered in asub-therapeutic dose. In still other embodiments, rivastigmine or apharmaceutically acceptable salt thereof, can be administered in asub-therapeutic dose, while the additional therapeutic agent isadministered in an effective amount.

As used herein, the terms “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more prophylactic and/or therapeutic agents). The use of theterms does not restrict the order in which therapies (e.g., prophylacticand/or therapeutic agents) are administered to a person in need thereof.

Co-administration encompasses administration of the first and secondamounts of therapeutic compounds in an essentially simultaneous manner,such as in a single pharmaceutical composition, for example, anintranasal spray having a fixed ratio of first and second amounts. Inaddition, such co-administration also encompasses use of each compoundin a sequential manner in either order. When co-administration involvesthe separate administration of the first amount of rivastigmine or apharmaceutically acceptable salt thereof, and a second amount of anadditional therapeutic agent, they are administered sufficiently closein time to have the desired therapeutic effect. For example, the periodof time between each administration which can result in the desiredtherapeutic effect, can range from minutes to hours and can bedetermined taking into account the properties of each compound such aspotency, solubility, bioavailability, plasma half-life, and kineticprofile. For example, rivastigmine or a pharmaceutically acceptable saltthereof, and the second therapeutic agent can be administered in anyorder within about 24 hours of each other, within about 16 hours of eachother, within about 8 hours of each other, within about 4 hours of eachother, within about 1 hour of each other, within about 30 minutes ofeach other, within about 15 minutes of each other, within about 10minutes of each other or within about 5 minutes of each other.

In one or more embodiments where the rivastigmine or a pharmaceuticallyacceptable salt thereof is administered with additional therapeuticagent, the agent may be any therapeutic agent which provides a desiredtreatment outcome. In particular, the additional therapeutic agent maybe selected from a sigma-1 receptor agonist, an NMDA antagonist, annicotinic acetylcholine receptor agonist and combinations thereof. Inparticular, sigma-1 receptor agonists in accordance with the presentinvention may include dextromethorphan or pharmaceutically acceptablederivatives thereof, including dextromethorphan hydrobromide; NMDAantagonists in accordance with the present invention may includememantine, ifenprodil, or pharmaceutically acceptable derivativesthereof, including memantine hydrochloride and ifenprodil tartrate;nicotinic acetylcholine receptor agonists in accordance with the presentinvention may include encenicline or pharmaceutically acceptablederivatives thereof, including encenicline hydrochloride.

Sigma-1 receptor agonists have been recognised to alleviate cognitivedeficits and reduce neuronal damage and are thus considered usefulagents in the treatment of Alzheimer's disease. U.S. Pat. No. 4,806,543describes the use of dextromethorphan as a neuroprotective agent in thetreatment of Alzheimer's disease and other neurodegenerative disorders,however its practical use as an oral dose form has been limited by bothits extensive first-pass metabolism to dextrorphan which can haveadverse psychoactive effects (Moghadamnia A A., et al. 2003, ZawertailoL A., et al. 2010; Miller S C., 2011). Furthermore, at high doses, oraldextromethorphan presents an abuse liability risk (Miller S C. 2005).While the addition of oral quinidine with oral dextromethorphan has beenknown to reduce the first-pass metabolism to dextrorphan, it has theadded disadvantage of increasing the risk of cardiac adverse events(Zawertailo L A., et al. 2010, Zawertailo L A. 2011). Accordingly, insome aspects the present invention provides a composition and use ofdextromethorphan in combination with rivastigmine, via simultaneous,sequential or separate intranasal administration. Systemic delivery ofdextromethorphan in combination with rivastigmine via intranasaladministration may advantageously reduce or alleviate one or more of thecore symptoms of a given neurodegenerative disorder, for example thesymptoms associated with Alzheimer's diseases or Parkinson's disease.

NMDA antagonists are a class of compounds which inhibit the action onthe N-Methyl-D-aspartate receptor. The N-Methyl-D-aspartate receptor isrecognised to play a role in the glutamatergic system via the NR2Bsub-unit and, as a target, is thought to offer an alterative approach totreatment of neurodegenerative diseases such as Alzheimer's orParkinson's diseases. NMDA antagonists typically induce a state calleddissociative anesthesia. Suitable NMDA antagonists in accordance withthe present invention may include memantine, ifenprodil, orpharmaceutically acceptable derivatives thereof, such as memantinehydrochloride and ifenprodil tartrate. Memantine has been recognised toalleviate symptoms associated with moderate-to-severe Alzheimer'sdisease and is also thought to have activity as a non-competitiveantagonist at acetylcholine receptors (nAChRs). Ifenprodil has beenshown to exhibit activity at the NR2B subunit of the NMDA receptor(Schepmann D., et al. 2010) and may thus alleviate symptoms associatedwith neurodegenerative diseases such as Alzheimer's disease. U.S. Pat.No. 5,543,421 describes the use of ifenprodil for treating centralneurodegenerative diseases in a patient with a dose as low as 1 mg aday. Suitable ifenprodil salts, including neutral tartrate and acidtartrate, have been originally described in U.S. Pat. No. 3,509,164.Without wishing to be bound by theory, it is considered that concernsregarding a lack of selectivity with regard to NMDA antagonists such asifenprodil may be avoided with low-dose systemic therapy, such asintranasal delivery (Mony L., et al. 2009). Accordingly, in some aspectsthe present invention provides a composition and use of an NMDAantagonist in combination with rivastigmine, via simultaneous,sequential or separate intranasal administration. Systemic delivery ofNMDA antagonists, including memantine, ifenprodil, or pharmaceuticallyacceptable derivatives thereof, such as memantine hydrochloride andifenprodil tartrate, in combination with rivastigmine via intranasaladministration may advantageously reduce or alleviate one or more of thecore symptoms of a given neurodegenerative disorder, for example thesymptoms associated with Alzheimer's diseases or Parkinson's disease.

Nicotinic acetylcholine receptor agonists are a class of compounds thatbind to nicotinic acetylcholine receptors in the central nervous system,the peripheral nervous systems, skeletal muscles and combinationsthereof. Nicotinic acetylcholine receptor agonists are considered to besuitable candidates for treatment of central nervous system disorders,including Alzheimer's disease, Parkinson's disease, schizophrenia, andattention-deficit hyperactivity disorder. Specifically, the use ofnicotinic acetylcholine receptor agonists, in particular alpha-7nicotinic acetylcholine receptor agonists, is considered to improvecognitive function in patients with Alzheimer's disease (Posadas I., etal. 2013). Suitable nicotinic acetylcholine receptor agonists inaccordance with the present invention include encenicline orpharmaceutically acceptable derivatives thereof, including enceniclinehydrochloride. The intranasal delivery of nicotinic acetylcholinereceptor agonists has been described in U.S. Pat. No. 8,710,227, thecontents of which is incorporated herein by reference. Accordingly, insome aspects the present invention provides a composition and use of anicotinic acetylcholine receptor agonist in combination withrivastigmine, via simultaneous, sequential or separate intranasaladministration. Systemic delivery of nicotinic acetylcholine receptoragonists, including encenicline or pharmaceutically acceptablederivatives thereof, such as encenicline hydrochloride, in combinationwith rivastigmine via intranasal administration may advantageouslyreduce or alleviate one or more of the core symptoms of a givenneurodegenerative disorder, for example the symptoms associated withAlzheimer's diseases or Parkinson's disease.

Where rivastigmine is administered in combination with an additionaltherapeutic agent, the second agent may be administered in any“effective amount” which provides the desired therapeutic activity, asdescribed above. Suitable dosage amounts and dosing regimens of theadditional therapeutic agent can be determined by the attendingphysician and may depend on the particular condition being treated, theseverity of the condition as well as the general age, health and weightof the subject. It will be appreciated that dose ranges as describedherein provide guidance for the administration of providedpharmaceutical compositions to an adult. The amount to be administeredto can be determined by a medical practitioner or person skilled in theart.

For example, suitable systemic doses of dextromethorphan to be used incombination with rivastigmine may be arrived at based on the potency ofdextromethorphan as a sigma one receptor agonist. Specifically,dextromethorphan is recognised as having a dissociation constant (K_(d))of 20 nM in binding studies with rat brain (Klein and Musacchio 1992),equivalent to about 5.4 ng/mL of dextromethorphan. Additionally, thephysicochemical properties of dextromethorphan advantageously enable itto readily cross the blood-brain barrier. Assuming an average targetplasma concentration of about 5.4 ng/mL and a systemic clearance ofabout 23 mL/min/kg for example (Kukanich and Papich 2004; Davies andMorris 1993), an effective systemic dose of dextromethorphan as the freebase may be in the range of about 1 to about 25 mg per day, preferablyabout 3 to about 20 mg per day, more preferably about 5 to about 18 mgper day, in particular about 10 to about 15 mg per day, for example,about 12 mg per day.

Accordingly, in one or more embodiments the present invention providesan intranasal composition comprising rivastigmine and dextromethorphan,or a pharmaceutically acceptable salt thereof, includingdextromethorphan hydrobromide, wherein the dextromethorphan is in anamount of from about 0.5 to about 15% by weight of the totalcomposition, preferably from about 1 to about 10% by weight of the totalcomposition, more preferably from about 1 to about 7% by weight of thetotal composition, in particular from about 2 to about 5% by weight ofthe total composition.

In one or more other embodiments, the present invention provides anintranasal composition comprising rivastigmine and encenicline, or apharmaceutically acceptable salt thereof, including enceniclinehydrochloride, wherein the encenicline is in an amount of from about0.25 to about 7% by weight of the total composition, preferably fromabout 0.5 to about 4% by weight of the total composition, morepreferably from about 1 to about 3% by weight of the total composition.

With regard to ifenprodil, its use as a low-dose oral dosage formulationis limited by its extensive first-pass metabolism and associatedvasodilator effect at higher doses such as, 40 to 60 mg orally daily, or15 mg i.v. daily, when treating peripheral vascular disease (Falck E. etal. 2014; Saitoh K. et al. 1987, Martindale 35th Ed. p 1179.2). Theintranasal delivery of ifenprodil may advantageously address one or moreof these deficiencies. Accordingly, in one or more further embodiments,the present invention provides an intranasal composition comprisingrivastigmine and ifenprodil, or a pharmaceutically acceptable saltthereof, including ifenprodil tartrate, wherein the ifenprodil is in anamount of from about 0.001 to about 5% by weight of the totalcomposition, preferably from about 0.005 to about 2% by weight of thetotal composition, more preferably from about 0.01 to about 1% by weightof the total composition, in particular from about 0.1 to about 0.5% byweight of the total composition.

Furthermore the intranasal delivery of dextromethorphan in combinationwith rivastigmine, may provide improved bioavailability when comparedwith oral delivery of dextromethorphan alone (Moghadamnia A A., et al.2003).

The intranasal compositions of the present invention may be administeredin a single dose or a series of doses. While it is possible for thecomposition to be administered alone, in some embodiments it may bepreferable to present it as a pharmaceutical formulation.

In one or more embodiments, the intranasal compositions according to thepresent invention may be prepared as pharmaceutically acceptableemulsions, microemulsions, solutions, or suspensions In particular, thecompositions of the present invention may be prepared as aqueoussolutions or suspensions. In one or more embodiments, the presentinvention provides an aqueous solution comprising rivastigmine forintranasal administration. Where the formulations of the presentinvention are aqueous solutions or suspensions, the formulations maycomprise water is in an amount of greater than 50% by weight of thetotal composition, preferably greater than about 60% by weight of thetotal composition, more preferably greater than about 70% by weight ofthe total composition, even more preferably greater than about 80% byweight of the total composition. In still other embodiments, where theformulations of the present invention are aqueous solutions orsuspensions, the formulations may comprise water in the range of fromabout 80% to about 99% by weight of the total composition, morepreferably from about 85% to about 98% by weight of the totalcomposition.

In addition to the active ingredients, the liquid dosage forms maycomprise inert diluents commonly used in the art such as, for example,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils(e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesameoils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols andfatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the intranasal compositions may include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents. It is recognised that the additionalinert diluents may also act as, for example, penetration enhancers,thickening agents, or co-solvents within the scope of the presentinvention, as previously described.

Where a carrier is used, the carrier must be pharmaceutically“acceptable” in the sense of being compatible with the other ingredientsof the composition and not injurious to the subject.

General considerations in formulation and/or manufacture ofpharmaceutical intranasal compositions agents can be found, for example,in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin(Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science andPractice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins,2005).

Pharmaceutical compositions for intranasal administration in accordancewith the invention can be prepared by any method known in the art ofpharmacology. In general, such preparatory methods include the steps ofbringing the compound of the present invention (the “active ingredient”)into association with a carrier and/or one or more other accessoryingredients, and then, if necessary and/or desirable, shaping and/orpackaging the product into a desired single- or multi-dose unit.

As used herein, a “unit dose” is discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

The formulations in accordance with the invention may be administered toa person in need thereof by any suitable intranasal delivery methods.Suitable methods for intranasal administration would be well-known to aperson skilled in the art. The intranasal compositions disclosed hereincan be administered as a spray or drop. Accordingly, suitable commercialpackages containing the intranasal formulation can be in any spraycontainer known in the art. In one or more embodiments, the formulationsin accordance with the invention may be administered via a spray deviceor container. Spray devices in accordance with the invention may besingle unit dose systems or multiple dose systems, for examplecomprising a bottle, a pump and/or an actuator. Such spray devices areavailable commercially. Suitable commercial spray devices include thoseavailable from Nemera, Aptar, Bespak and Becton-Dickinson. In stillother embodiments, the formulations in accordance with the invention maybe administered via an electrostatic spray device, such as described inU.S. Pat. No. 5,655,517. Other suitable means for administeringformulations intranasally in accordance with the invention include via adropper, a syringe, a squeeze bottle, and any other means known in theart for applying liquids to the nasal mucosa in an accurate andrepeatable fashion.

The spray devices used to administer the composition can range fromsingle-use metered-dose spray devices, multiple-use metered dose nasalspray devices and are not limited to spraying the solutions into eachnaris but can be administered as a gentle liquid stream from a plunger,syringe or the like or as drops from a unit-dose or multi-dose squeezebottle, or other means known in the art for applying liquids to thenasal mucosa in an accurate and repeatable fashion.

In one or more embodiments, a spray device in accordance with theinvention may typically deliver a volume of liquid in a single sprayactuation in the range of from 0.01 to 0.15 mL. A typical dosing regimenfor a nasal spray product may be in the range of one spray into a singlenostril (naris) to two sprays into each nostril (naris). Repeat dosingof the same nostril (naris) may also be undertaken. It is recognisedthat the dosing schedule, including a repeat dosing schedule, may bemodified to obtain a desired pharmacokinetic profile. In one or moreembodiments, repeat dosing may occur every 1 hour, 2 hours, 3 hours, 4hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. Inparticular, repeat dosing may occur during waking hours. Morepreferably, repeat dosing in accordance with the invention may occurevery 2, 4, 6 or 8 hours during waking hours.

The amount of rivastigmine administered per dose or the total volume ofcomposition administered will depend on such factors as the nature andseverity of the symptoms, the age, weight, and general health of thepatient. In still other embodiments, repeat dosing may occur where apatient does not adequately respond to an initial dose, for example, byalleviation of one or more symptoms of dementia. In some embodiments,the intranasal pharmaceutical composition may deliver a unit dose ofrivastigmine selected from about 0.05 to about 20 mg, about 0.10 toabout 15 mg, about 0.15 to about 6 mg, about 0.2 to about 5 mg, about0.3 to about 3 mg, about 0.6 to about 2.5 mg, about 1 to about 2 mg;about 1.25 to about 1.75 mg.

It is recognised that relative amounts of excipients, solvents,diluents, salts, thickening agents, sensory agents, buffers, and/or anyadditional ingredients in a pharmaceutical composition of the inventionwill vary, depending upon the identity, size, and/or condition of thesubject treated.

In certain embodiments, unit dosage compositions are those containing adaily dose or unit, daily sub-dose, as herein above described, or anappropriate fraction thereof, of the active ingredient.

The intranasal formulations in accordance with the present invention maybe contained in a kit. The kit may include, for example, rivastigmineand an additional agent, each packaged or formulated individually forintranasal administration, or packaged or formulated in combination.Thus, rivastigmine may be present in first container, and the kit canoptionally include one or more agents in a second container. Thecontainer or containers are placed within a package, and the package canoptionally include administration or dosage instructions. A kit caninclude additional components such as syringes or other means foradministering the agents as well as diluents or other means forformulation. Thus, the kits can comprise: a) a pharmaceuticalcomposition comprising rivastigmine described herein and apharmaceutically acceptable carrier, vehicle or diluent; and b) acontainer or packaging. The kits may optionally comprise instructionsdescribing a method of using the pharmaceutical compositions in one ormore of the methods described herein (e.g. preventing or treating one ormore of the diseases and disorders described herein). The kit mayoptionally comprise a second pharmaceutical composition comprising oneor more additional agents described herein for co therapy use, apharmaceutically acceptable carrier, vehicle or diluent. Thepharmaceutical composition comprising rivastigmine and the secondpharmaceutical composition contained in the kit may be optionallycombined in the same pharmaceutical composition.

It may be desirable to provide written memory aid containing informationand/or instructions for the physician, pharmacist or subject regardingwhen the medication is to be taken. An example of such a memory-aid is amechanical counter which indicates the number of daily doses that havebeen dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

In some aspects, rivastigmine could be provided in the form of aprodrug. The term “pro-drug” is used in its broadest sense andencompasses those derivatives that are converted in vivo to thecompounds of the invention. Such derivatives would readily occur tothose skilled in the art.

Furthermore, it is recognised that rivastigmine may be in crystallineform either as the free compound or as a solvate (e.g., hydrates) and itis intended that both forms are within the scope of the presentinvention. Methods of solvation are generally known within the art.

Those skilled in the art will be aware that the invention describedherein is subject to variations and modifications other than thosespecifically described. It is to be understood that the inventiondescribed herein includes all such variations and modifications. Theinvention also includes all such steps, features, methods, compositionsand compounds referred to or indicated in this specification,individually or collectively, and any and all combinations of any two ormore of said steps or features.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

Certain embodiments of the invention will now be described withreference to the following examples which are intended for the purposeof illustration only and are not intended to limit the scope of thegenerality hereinbefore described.

EXAMPLES Example 1: Diffusion Studies with Bovine Nasal Mucosa Over 6Hours

Freshly excised, full-thickness, adult bovine nasal mucosa was placedinto horizontal flow-through diffusion cells with a diffusional area of1.0 cm² (Permegear, US). The mean thickness of the excised nasal mucosaused in the diffusion experiments for Formulations 1 to 4 was 760±40 μm(mean±SE, n=32). Following excision, the bovine nasal mucosa was floatedin PBS at room temperature whilst awaiting placement in the diffusioncell. After placement in the diffusion cell, the surface of the nasalmucosa was gently blotted with a fine grade absorbable wipe to removeany excess PBS from the surface of the nasal mucosa. Diffusionexperiments were performed over 12 to 24 h time periods. The receptorsolution consisted of PBS, which was degassed under vacuum prior to thediffusion experiment. Eight diffusion cells were maintained at a flowrate of 1.3 ml/h by a microcassette peristaltic pump operating with 0.38mm i.d. tubing (Watson Marlow 205S with O/G Marprene manifold tubing,UK) which ensured sink conditions were maintained. The cells were keptat 31° C. with a heater bar (Permegear, US) connected to a circulatingwater heater (Thermoline TU1, Australia). Samples were collected into6.5 ml PP vials (Simport snaptwist, US) housed on an automated fractioncollector (Teledyne Isco Retriever 500, US). Prior to analysis byRP-HPLC each vial was weighed on an analytical balance (ShimazduAUW220D) connected to a personal computer and then the volume calculatedin each vial from the density of the receptor solution which was about1.0 g/cm³. The nasal spray solutions were applied to the nasal mucosa ofeach diffusion cell with a 0.5 to 10 μL adjustable pipette (MettlerToledo L-10XLS) at a dose volume of 5 μL per cm² unless otherwisestated.

The compositions of Formulations 1 to 4 are detailed in Table 1.Formulation 4, comprising an aqueous solution of rivasitgmine in citratebuffer at pH 3.65 was used as a control. The mean cumulative amount ofrivastigmine (Q Riv) diffused after 6 hours across bovine nasal mucosain vitro for each of Formulation 1 to 4 is detailed in Table 2.

TABLE 1 Composition of Formulations 1 to 4 Control Formulation 1Formulation 2 Formulation 3 Formulation 4 Rivastigmine 2.5% w/v 2.5% w/v2.5% w/v 2.5% w/v tartrate Citric acid 0.05% w/v 0.05% w/v 0.05% w/v0.05% w/v monohydrate Sodium citrate 0.25% w/v to a 0.25% w/v to a 0.25%w/v to a 0.25% w/v to a measured measured measured measured aqueousbuffer aqueous buffer aqueous buffer aqueous buffer pH of 3.65 pH of3.65 pH of 3.65 pH of 3.65 Carveol 0.05% v/v — 0.05% v/v — Ethanol 10%v/v — 10% v/v — Benzyl alcohol 0.65% v/v — 0.65% v/v — USP Povidone 1.0%w/v 1.0% w/v — — Purified water to volume (100 to volume (100 to volume(100 to volume (100 mL) mL) mL) mL)

TABLE 2 Mean cumulative amount of rivastigmine (Q Riv) after 6 hoursacross bovine nasal mucosa in vitro Q Riv 6 h % of Formulation (μg/cm² ±SE, Applied No. n = 8) Dose 1  49 ± 3*  63* 2 42 ± 7 54 3 44 ± 5 56 4(control) 38 ± 4 49 *Statistically significantly different to4(control),p < 0.01

TABLE 3 Mean cumulative amount of rivastigmine (Q Riv) after 12, 18 and24 hours across bovine nasal mucosa in vitro Dose Time (h) to Q Riv % ofFormulation applied finite dose (μg/cm² ± SE, Applied Dose No. (μL/cm²)depletion n = 4) at depletion Dose Proportionality 1 5 12  60 ± 9 77 1 110 18 142 ± 3 91 2.4 3 5 12  57 ± 7 73 1 3 10 16 121 ± 6 78 2.1 3 20 24307 ± 9 98 5.4 Dose Proportionality, ratio of Q Riv divided by Q Riv forthe lowest dose (i.e. 5 μL)

The mean cumulative amount of rivastigmine (Q Riv) that had diffusedacross the bovine nasal mucosa in vitro was measured after 6 hours wassignificantly greater (p<0.01) for Formulation 1 (round symbols) whencompared with the control Formulation 4 (square symbols) over the sametime period (Refer to FIG. 1, Tables 1 and 2). At 6 hours post-dose, themean percentage of the applied dose penetrated was 63% and 49% forFormulation 1 and control Formulation 4, respectively (p<0.01).Formulation 1 provided a statistically significant 30% increase in the QRiv after 6 hours (p<0.01).

Formulation 2, comprising an aqueous solution of rivastigmine in citratebuffer at pH 3.65 and thickening agent povidone was also compared withcontrol Formulation 4 (Refer to Table 1 and 2). The addition of thethickening agent (Formulation 2) improved the diffusion of rivastigmineacross nasal mucosa compared with the control formulation that containeddrug and a citric acid pH modifier alone (Formulation 4).

Formulation 3, comprising an aqueous solution of rivastigmine in citratebuffer at pH 3.65, sensory agents (ethanol and carveol) and apreservative (benzyl alcohol) was also compared with control Formulation4 (Refer to Table 1 and 2). The addition of the sensory agents, andpreservative (Formulation 3) also improved the diffusion of rivastigmineacross nasal mucosa compared with the control formulation that containeddrug and a citric acid pH modifier alone (Formulation 4).

Example 2: Diffusion Studies with Bovine Nasal Mucosa Over 12 Hours

The mean cumulative amount of rivastigmine (Q Riv) that had diffusedacross the bovine nasal mucosa in vitro was also assessed after 12 hoursfor Formulation 1 (round symbols) when compared with the controlFormulation 4 (square symbols; Refer to FIG. 2). Finite dose depletionof the diffusion profile was observed after 12 hours, with Q Riv at 12hours for Formulation 1 (60±9 μg/cm², n=4) significantly greater(p<0.04) when compared with control Formulation 4 (52±6 μg/cm², n=8). At12 hours post-dose, the formulation of Formulation 1 provided astatistically significant 16% increase in the Q Riv (p<0.04), the meanpercentage of the applied dose penetrated was about 77% and 66% forFormulation 1 and control Formulation 4, respectively (p<0.04).

Example 3: Repeat Dosing Diffusion Studies with Bovine Nasal Mucosa at 0and 6 Hours

Repeat dosing of Formulation 1 at 0 and 6 hours (5 μL dose at each oft=0 and 6 hours) resulted in diffusion profiles that were zero-order innature (Refer to FIG. 3). Individual diffusion profiles (n=4) eachproduced statistically significant linear regressions (r² range=0.962 to0.987; F range=178 to 539; all p-values<0.001) when plotted from zero to12 hours. The mean flux for Formulation 1 over 12 hours with repeatdosing was 11±1 μg/cm²·h (mean±SE, n=4). FIG. 3 details the results of QRiv for Formulation 1 (round symbols, n=4) and Formulation 2 (squaresymbols, n=4) with repeat dosing schedule. The mean percentage of theapplied dose penetrated was about 91% and 82% respectively forFormulation 1 and Formulation 2, respectively (p<0.04).

Example 4: Diffusion Studies with Bovine Nasal Mucosa Over 24 Hours

Following a single 20 μL/cm² dose of Formulation 3 to each diffusioncell (round symbols), the finite dose depletion of the diffusion profilewas observed after 24 hours (Refer to FIG. 4). Q Riv at 6 hours, 12hours and 24 hours for Formulation 3 was 222±22, 286±14 and 307±9 μg/cm²(n=4), respectively, or 71%, 91% and 98% of the applied dose,respectively. Freshly excised, bovine nasal mucosa is an accepted invitro model to study drug permeability of the nasal epithelium (Schmidtet al. 2000) and can be used to estimate the systemic bioavailability inhumans of compounds administered intranasally (Chemuturi et al. 2005). Adrawing of the flow-through diffusion cell is shown in FIG. 5. Thereliability of the dose proportionality of the in vitro bovine nasalmucosa model is shown by Table 3, where a doubling of the dose appliedfor each of Formulations 1 and 3 led to similar proportional increasesin Q Riv. Without wishing to be bound by theory, the diffusion profilesobtained for the previous examples where consistent with Fick's secondlaw of diffusion after a finite dose to the apical surface of a nasalmembrane.

Example 5: Combination Intranasal Spray Comprising Rivastigmine andDextromethorphan

Detailed in Table 4 is an example of an intranasal formulationcomprising rivastigmine tartrate and dextromethorphan hydrobromidewithin the same intranasal spray composition.

TABLE 4 Component % composition Rivastigmine tartrate 2.0% w/vDextromethorphan 3.0% w/v hydrobromide Citric acid monohydrate 0.05% w/vSodium citrate 0.25% w/v to a measured aqueous buffer pH of 3.65 Carveol0.05% v/v Ethanol 10% v/v Glycerol 30% v/v Benzyl alcohol 0.65% v/vPurified water to volume (100 mL)

Example 6: Intranasal Spray Comprising Dextromethorphan forCo-Administration

Detailed in Table 5 is an example of an intranasal formulationcomprising dextromethorphan hydrobromide which may be co-administered incombination with a rivastigmine intranasal spray composition, such asthat described in Formulation 1.

TABLE 5 Component % composition Dextromethorphan 2.0% w/v hydrobromideCitric acid monohydrate 0.05% w/v Sodium citrate 0.25% w/v to a measuredaqueous buffer pH of 3.65 Carveol 0.05% v/v Ethanol 10% v/v Glycerol 10%v/v Benzyl alcohol 0.65% v/v Purified water to volume (100 mL)

Example 7: Combination Intranasal Spray Comprising Rivastigmine andIfenprodil

Detailed in Table 6 is an example of an intranasal formulationcomprising rivastigmine tartrate, dextromethorphan hydrobromide andifenprodil hydrochloride within the same intranasal spray composition.

TABLE 6 Component % composition Rivastigmine tartrate 2.0% w/vDextromethorphan 3.0% w/v hydrobromide Ifenprodil hydrochloride 0.25%w/v Citric acid monohydrate 0.05% w/v Sodium citrate 0.25% w/v to ameasured aqueous buffer pH of 3.65 Carveol 0.05% v/v Ethanol 10% v/vGlycerol 30% v/v Benzyl alcohol 0.65% v/v Purified water to volume (100mL)

Example 8: Intranasal Spray Comprising Ifenprodil for Co-Administration

Detailed in Table 7 is an example of an intranasal formulationcomprising ifenprodil hydrochloride which may be co-administered incombination with a rivastigmine intranasal spray composition, such asthat described in Formulation 1.

TABLE 7 Component % composition Ifenprodil hydrochloride 0.25% w/vCitric acid monohydrate 0.05% w/v Sodium citrate 0.25% w/v to a measuredaqueous buffer pH of 3.65 Carveol 0.05% v/v Ethanol 10% v/v Glycerol 10%v/v Benzyl alcohol 0.65% v/v Purified water to volume (100 mL)

Example 9: Combination Intranasal Spray Comprising Rivastigmine andEncenicline

Detailed in Table 8 is an example of an intranasal formulationcomprising rivastigmine tartrate and encenicline hydrochloride withinthe same intranasal spray composition.

TABLE 8 Component % composition Rivastigmine tartrate 2.0% w/vEncenicline hydrochloride 1.5% w/v Citric acid monohydrate 0.05% w/vSodium citrate 0.25% w/v to a measured aqueous buffer pH of 3.65 Carveol0.05% v/v Ethanol 10% v/v Glycerol 10% v/v Benzyl alcohol 0.65% v/vPurified water to volume (100 mL)

Example 10: Intranasal Spray Comprising Encenicline forCo-Administration

Detailed in Table 9 is an example of an intranasal formulationcomprising encenicline hydrochloride which may be co-administered incombination with a rivastigmine intranasal spray composition, such asthat described in Formulation 1.

TABLE 9 Component % composition Encenicline hydrochloride 2.0% w/vCitric acid monohydrate 0.05% w/v Sodium citrate 0.25% w/v to a measuredaqueous buffer pH of 3.65 Carveol 0.05% v/v Ethanol 10% v/v Benzylalcohol 0.65% v/v Purified water to volume (100 mL)

Example 11: Intranasal Spray Comprising Rivastigmine

Detailed in Table 10 is an example of an intranasal formulationcomprising rivastigmine tartrate at a higher concentration.

TABLE 10 Component % composition Rivastigmine tartrate 5.0% w/v Citricacid monohydrate 0.055% w/v Carveol 0.05% v/v Ethanol 10% v/v Benzylalcohol 0.65% v/v Polyvinyl pyrrolidone 1.0% w/v Purified water tovolume (100 mL)

Example 12: Absolute Bioavailability and Safety Study of RivastigmineIntranasal Spray in Healthy Elderly Individuals Methods

The safety and absolute bioavailability of an intranasal formulation inaccordance with the invention was examined by clinical trial. The studywas approved by The Alfred Hospital Human Research and Ethics Committee,Melbourne, Australia and prospectively registered with the Australia andNew Zealand Clinical Trial Registry (ANZCTR), Trial IDACTRN12614001313628. The study was conducted at the clinical trial unitof Nucleus Network Limited (Melbourne, Australia) and independentlymonitored by Commercial Eyes Pty Ltd (Melbourne, Australia) inaccordance with Good Clinical Practice (GCP) and the principles of theDeclaration of Helsinki.

Design

The study was of open label, sequential, crossover design in eighthealthy elderly female and male Caucasian volunteers who all gavewritten informed consent to participate in the study. On day 1,intravenous rivastigmine (1 mg) was administered to each participant asa constant intravenous infusion over 30 minutes, followed by a washoutperiod of two days (days 2 and 3). On day 4, a rivastigmine intranasalspray (3.126 mg) was administered to each participant as a single dosecomprising one spray in each nostril.

Key inclusion criteria for participation in the study included:

-   -   Healthy Caucasian males and females between 55 and 85 years        (inclusive) of age;    -   No known history of clinically significant neurological, renal,        cardiovascular, respiratory (asthma), endocrinological,        gastrointestinal, haematopoietic disease, neoplasm or any other        clinically significant medical disorder, which in the Principal        Investigator's judgment contraindicate administration of the        study interventions;    -   BMI 18-32 (inclusive) calculated as Weight (kg)/Height (m²)    -   Non-smoking (by declaration) for a period of at least 6 months.

Key exclusion criteria included:

-   -   Known hypersensitivity to the drug, components (benzyl alcohol,        benzoates) or other carbamates;    -   Current symptomatic allergic rhinitis;    -   History of or currently active asthma or chronic obstructive        pulmonary disease, excluding childhood asthma;    -   History of or currently active cardiac arrhythmias such as        bradycardia and sick sinus syndrome;    -   History of urinary tract obstruction;    -   History of or currently active GI diseases such as peptic ulcer,        GERD, bleeding or history of any GI surgery other than        appendectomy or herniotomy, or with any gastrointestinal        disorder likely to influence drug absorption, or with any        history of anorexia, frequent nausea or emesis, regardless of        etiology;    -   Use of any beta-blocker class prescription drug, cholinomimetic        and anticholinergic drugs, including atropine, tricyclic        antidepressants and anti-histamines.

Clinical

Detailed in Table 11 is the intranasal spray formulation in accordancewith the invention administered during the clinical trial:

TABLE 11 Component % composition Rivastigmine tartrate 2.5% w/v Citricacid monohydrate 0.055% w/v Carveol 0.05% v/v Ethanol 10% v/v Benzylalcohol 0.65% v/v Polyvinyl pyrrolidone 1.0% w/v Distilled water tovolume

The abovementioned formulation was filled into 20 ml high-densitypolyethylene bottles and sealed with 100 μL VP7 metered-dose pump valveswith nasal spray actuators and caps (Aptar, Le Vaudreuil, FR) and had afinal pH of 3.6. One 100 μL spray (2.5 mg rivastigmine tartrateequivalent to 1.563 mg rivastigmine free base) was administered intoeach nostril by study staff for a total single-dose of 3.126 mgrivastigmine. The shot weight delivered to each participant wasdetermined by weighing the intranasal spray device before and after eachdosing each participant. The amount of rivastigmine delivered to eachparticipant was determined from the shot weight, density andconcentration of the intranasal spray formulation.

Detailed in Table 12 is the solution of rivastigmine administeredintravenously as a control in the clinical trial:

TABLE 12 Component % composition Rivastigmine tartrate 0.032% w/v Citricacid monohydrate 0.022% w/v Distilled water To provide 1 mg rivastigmineper 5 mL

The abovementioned solution was sterilised by filtration thenaseptically filled into sealed type 1 glass vials. For intravenous(i.v.) administration, 6 ml of the i.v. solution was diluted to 30 mlwith 5% glucose for injection and 25 ml (1 mg rivastigmine) wasadministered as a constant infusion over 30 min using a volumetricallycontrolled syringe driver. The infusion line was primed prior to startof the infusion.

Blood samples were taken from the non-dominant arm of each participanti) for the i.v. treatment at time point 0 (pre-administration), 10 min,20 min, 30 min, 45 min, 60 min, 75 min, 90 min; 2 h, 3 h, 4 h, 6 h, 8 h,12 h and 24 h post-administration, and ii) for the intranasal treatmentat time point 0 (pre-administration), 5 min, 10 min, 15 min, 30 min, 60min, 90 min; 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h and 24 hpost-administration.

Blood was collected into K₂ EDTA tubes, and immediately transferred to apre-chilled polypropylene centrifuge tube, containing sodium fluoride(110 μL of a 1M sodium fluoride solution per 1 mL blood) to inhibit anyex vivo enzymatic breakdown of the parent compound and its metabolite.The whole blood sample was centrifuged at 3000 rpm (about 1900 g), 3° to5° C., for 10 min, and the harvested plasma transferred to apolypropylene cryo-tube and stored frozen at −20° C. pending analysis.

Visual nasal mucosal examination occurred at screening, check-in, on day4 (pre-nasal-dose) and day 5 (24 hours post-nasal-dose). Adverse eventsand vital signs (blood pressure, heart rate, respiratory rate, oral bodytemperature) were monitored from Day 1 until Day 5 (24 hourspost-nasal-dose) and at follow-up visit (Day 9+/−1). For the elicitationof potential adverse events relating to nasal mucosal irritation aseries of relevant tolerability questions (stinging, itching, burningsensations in nose or throat, rhinalgia and lacrimation) were soughtfrom the participants with a 5-point Likert-scale for the responsesusing a perceived nasal irritation questionnaire. This assessment wascompleted at 20 and 75 minutes following the intranasally administereddose. Participants rated perceived nasal irrigation across the followingcriteria: 1. Stinging in the nose; 2. Itching in the nose; 3. Burningthe nose; 4. Causing a runny nose; 5. Stinging in the throat; 6. Itchingin the throat; 7. Burning in the throat; and 8. Causing watery eyes.Participants graded each criterion according to the following scale: i)Not at All; ii) Mildly; iii) Moderately; iv) Somewhat markedly; or v)Very Markedly.

A healthy screen pre- and post-study was completed for all participants.The healthy screen included:

-   -   Physical examination, including vital signs (blood pressure,        heart rate, respiratory rate and temperature) and ECG;    -   Urinalysis for general health (urine pH, blood, protein,        ketones, leukocyte elastase, nitrates, glucose, Specific        gravity, urobilinogen and bilirubin) and any drugs of        addiction*. Blood collected for clinical laboratory analysis        (serum chemistry and haematology) and analysis for HIV*,        hepatitis B*, and hepatitis C* analysis.    -   Normal ranges for clinical laboratory parameters will be as per        the local laboratory definitions (*pre-study).

Bioanalytical Assay

Analysis of rivastigmine and its primary metabolite,3-[(1S)-1-(dimethylamino)ethyl]phenol (hereafter “NAP 226-90”) wasperformed by the bioanalytical division of Anapharm Europe (Barcelona,SP). Rivastigmine, NAP 226-90 and internal standards were extracted froman aliquot of human EDTA plasma using a liquid-liquid extractionprocedure with ethyl acetate and then injected into a liquidchromatograph equipped with a tandem mass spectrometry detector(LC/MS/MS). Separations were performed on a reversed-phase column(Zorbax SB-C18, 4.6×50 mm, 5 μm, from Agilent Technologies). Mobilephase A was ammonium acetate 10 mM at pH 5 prepared in water and mobilephase B was ammonium acetate 10 mM prepared in methanol. Thechromatographic separation was gradiently performed at room temperatureat a flow-rate from 1.00 to 1.10 mL/min. The calibration range used forthis assay was from 0.05 to 20 ng/mL for rivastigmine and from 0.05 to10 ng/mL for NAP 226-90. The assay passed linearity for rivastigmine(r>0.997) and NAP226-90 (r>0.997) over each of the calibration rangestested. Accuracy and precision at the LLOQ (0.05 ng/mL) for rivastigminewere 5.65% and ±2.72%, respectively. Accuracy and precision at the LLOQ(0.05 ng/mL) for NAP226-90 were 5.79% and ±2.72%, respectively.Precision and accuracy for all the remaining concentrations in eachcalibration range were also within their acceptance limits.

Non-Compartmental Pharmacokinetic Analysis

Area under the curve (AUC) was taken from the blood plasmaconcentration-time profile. AUC to the last measured concentration(AUC0-1), AUC over a time interval (AUC0-6 h) and AUC zero to infinity(AUC0-∞) were calculated by the linear trapezoidal rule using Sigmaplot(version 12.5; Systat Software, Inc. San Jose, USA). The maximum plasmaconcentration (C_(max)) and time to maximum plasma concentration(T_(max)) were determined by visual inspection of the data. Absolutebioavailability (F) was calculated as AUC0-∞ nasal/nasal dose divided byAUC0-∞ i.v./i.v. dose. Terminal elimination half-life (t_(1/2)) wasdefined as 0.693/λ, where λ is the terminal elimination rate constant(calculated from the slope of the regression line of the terminal phaseof the natural logarithm of concentration versus time). Average plasmaconcentration (C_(avg)) was calculated from the AUC over a time interval(AUC_(0-6 h)) divided by the prospective dosage interval (6 h).Fluctuation index (FI) equalled (C_(max)−C_(min)) divided by C_(avg0-1).C_(avg0-1) was calculated as AUC0-1 divided by the time for the lastmeasured concentration. Metabolite (NAP226-90) to parent ratio wascalculated by dividing AUC0-∞ of NAP-226-90 divided by AUC0-∞ ofrivastigmine. Systemic clearance (CL=IV dose/AUC0-∞ i.v.) and volume ofdistribution (Vz=i.v. dose/λ●AUC0-∞ i.v.) were calculated for the i.v.dose.

Statistical Analysis

To meet the primary hypothesis that absolute bioavailability (F) is >0,a one-sample Student's t-test using a mean (SD) F=0.5 (0.25) and n=4,provides a Power of 0.908 when performed as a one-tailed test withalpha=0.050 using Sigmaplot analysis (version 12.5; Systat Software,Inc. San Jose, Calif., USA). This conservative (mean and variation)estimate for F, was based on the existing in vitro diffusion data forthe rivastigmine intranasal spray formulation and consideration of theextent and variability of nasal absorption in humans for other drugswith comparable physicochemical properties. Statistical significance wasdetermined by a one-sample Student's t-test, or a non-parametricone-sample Wilcoxon signed-rank test, if for example the raw F data arenot normally distributed. Pharmacokinetic parameters were tabulated asmean values with their standard deviation and percentage coefficient ofvariation (CV %).

Table 13 details the non-compartmental pharmacokinetic parameters ofrivastigmine after administration of rivastigmine 1 mg as a constantintravenous infusion or 3.126 mg intranasal spray in healthy elderlyindividuals (n=8).

TABLE 13 Rivastigmine Intranasal Spray Intravenous Solution ParameterMean ± SD CV % Range Mean ± SD CV % Range C_(max) (ng/mL)  6.9 ± 2.0 29 4.6-9.8    8.5 ± 1.8  22  5.8-11.2  T_(max) (h)  1.1 ± 0.5 46  0.5-2.0 0.5^(a) 0.5-0.5^(b)  0.2-0.5   AUC₀₋₁ 21.9 ± 6.3 29 13.2-31.9  11.5 ±1.4  12  8.7-13.7  (ng.h/mL) AUC_(0-∞) 22.6 ± 6.2 28 13.5-32.7  11.6 ±1.4  12   8.9-13.9  (ng.h/mL) t_(1/2) (h) 2.6^(a) 2.2-5.0^(b)  2.0-13.3  1.3 ± 0.1  8   1.2-1.4   F %   62 ± 15  25   45-85   Ref AUC_(0-6h)19.4 ± 5.7 30 11.8-27.5 (ng.h/mL) C_(avg0-6h)  3.2 ± 1.0 32  2.0-4.6 (ng/mL) FI 3.7^(a) 3.1-4.5^(b)  2.8-10.0 CL (L/h)  86.6 ± 11.9 14 71.8-112.2 Vz (L) 163.8 ± 25.6 16 131.5-210.8 ^(a)Median; ^(b)95% C.I.;Ref, Reference

Table 14 details the non-compartmental pharmacokinetic parameters ofNAP226-90 after administration of rivastigmine 1 mg as a constantintravenous infusion or 3.126 mg intranasal spray in healthy elderlyindividuals (n=8)

TABLE 14 Intranasal Intravenous NAP226-90 Spray Solution Parameter Mean± SD CV % Range Mean ± SD CV % Range C_(max) (ng/mL)  2.5 ± 0.6  24 2.0-3.4    1.2 ± 0.2  17   1.0-1.6   T_(max) (h)  2.1 ± 0.8  39 1.0-3.0    1.9 ± 0.6  32   1.3-3.0   AUC₀₋₁ 16.1 ± 2.2  14 12.8-19.1  6.7 ± 0.9  14   5.8-8.1   (ng.h/mL) AUC_(0-∞) 16.9 ± 2.3  14 13.8-20.5  7.2 ± 1.0  14   6.1-8.8   (ng.h/mL) t_(1/2) (h)  3.9 ± 0.8  21 2.9-4.6    2.8 ± 0.3  11   2.5-3.2   FI  2.8 ± 0.6  21  2.0-3.6 NAP226-90 0.78 ± 0.19 25 0.66-1.15  0.63 ± 0.11 18 0.46-0.79 AUC_(0-∞)to Rivastigmine AUC_(0-∞) ratio

The study met the primary endpoint because the mean absolutebioavailability (F) for rivastigmine intranasal spray was 62%,representing a statistically significant result (p<0.001) when testedagainst F>0. In this initial trial, the observed variability in nasalabsorption and metered-dosing was about 16%, while the non-dose adjustedpercentage coefficient of variation (CV %) for rivastigmine AUC0-∞ was28% and 12% for the intranasal and IV doses, respectively. Theintranasal spray in accordance with the invention exhibitedsignificantly (p<0.001) higher absolute bioavailability (62±15%, n=8)compared to the oral capsule (36±13%, n=12) and transdermal patch(45±10%, n=30; measured from post-usage drug residuals) in healthyelderly volunteers (Polinsky 1998, US FDA NDA No. 20-823, Lefèvre et al.2008a, US FDA NDA No. 22-083). The mean clearance (86.6 L/h) and volumeof distribution (163.8 L) for the 1 mg i.v. dose in this study waswithin the ranges previously observed for Alzheimer's disease patientsadministered a 2 mg i.v. dose (CL 21.6-82.8 L/h and Vz 53.2-227 L)(Hossain et al. 2002).

The initial clinical trial confirmed that rivastigmine, whenadministered as an intranasal formulation in accordance with theinvention, was rapidly absorbed across the nasal mucosa with a mean(±SD) T_(max) of 1.1±0.5 h and a mean C_(max) of 6.9±2.0 ng/mL. Theextent of absorption of rivastigmine was clinically significant.Furthermore, the results from this trial indicate that the C_(avg) overthe first 6 h after administration of the intranasal formulation couldreasonably be expected to have an appreciable inhibitory effect oncentral acetylcholinesterase levels in Alzheimer's disease patients(Cutler et al. 1998 and Gobburu et al. 2001).

The NAP226-90 to rivastigmine ratio for AUC0-∞ were 0.78±0.19 and0.63±0.11, for the intranasal and i.v. treatments, respectively. Thisratio is comparable to that previously measured for the transdermalpatch (0.67), and is advantageously 4-fold lower than the oral capsule(3.49) (Lefèvre et al. 2008a). It is generally recognised that a highdegree of first-pass metabolism in the liver and gut after oraladministration of rivastigmine results in much higher peripheralexposure to the metabolite (NAP226-90) (Polinsky 1998). The high F andlow NAP226-90: rivastigmine AUC ratio observed for the intranasal spraysin accordance with the invention are indicative that nasal absorption isthe dominant absorption pathway, and further suggests oral absorptiondue to nasal mucociliary clearance (Merkus et al. 1998) is limited.

Initial examination of single dose safety for rivastigmine intranasalsprays in accordance with the present invention indicate the solutionsare safe to administer with limited or no side effects. Only two minoradverse events relating to rivastigmine intranasal spray were recorded,i) one individual had mild nasal congestion and ii) a second individualhad a mild, red, itchy stomach rash. Both participants recovered within12 hours without treatment. Any minor nasal irritation or throatirritation was perceived by participants as mild and transient, and hadresolved at 20 minutes post-nasal-dose.

Advantageously, no nausea, vomiting and diarrhoea (NVD) was observedwith intranasal administration of rivastigmine despite the systemic dosebeing equivalent to a single 5.6 mg oral dose (i.e. 2.0 mg/Foral 0.355).Adverse gastrointestinal events (nausea, vomiting, diarrhea, weight lossand anorexia) have been significantly correlated with exposure to themetabolite NAP226-90 (both C_(max) and AUC) resulting from first-passmetabolism in the liver and gut after oral administration ofrivastigmine. No such correlation is associated with exposure torivastigmine itself in the absence of the metabolite (US FDA NDA No.20-823, Spencer and Noble 1998). The observed reduction or eliminationof adverse gastrointestinal side effects with intranasal administrationof rivastigmine represents a significant advantage. It has beensuggested low rivastigmine fluctuation index (FI) may reduceoral-related adverse gastrointestinal events by administration ofrivastigmine via a transdermal patch (median FI, 0.7; Kurz et al. 2009;Lefèvre et al. 2008b). However, advantageously, no NVD adverse eventswere observed even though the median rivastigmine FI (3.7) afterintranasal administration was similar to the median rivastigmine FI(4.2) after oral administration (Lefèvre et al. 2008b).

The metered-dose intranasal spray has inherent capability to provideimproved individual dosage adjustment within, below and above aneffective dosing range. This may be beneficial because the intrinsicclearance (CL) of rivastigmine varies up to 4-fold in Alzheimer'sdisease patients (Hossain et al. 2002). For example, variability inintrinsic clearance was observed in patients in the present study whoexhibited a mean i.v. intrinsic clearance 38% higher than that commonlyobserved in Alzheimer's disease (AD) patients (Hossain et al. 2002),consistent with other observations (29%, US FDA NDA No. 20-823). In suchcircumstances, it is recognised that a metered-dose intranasal spray inaccordance with the invention may advantageously provide improvedindividual dosage adjustment.

In the present clinical trial, an intranasal dose of two sprays (i.e.one 100 μL spray in each nostril) delivered a mean systemic rivastigminedose of 2 mg. For rivastigmine a few hours of the correctpharmacokinetic exposure in an Alzheimer's disease patient can provideup to half a day of central AChE inhibition (Cutler et al. 1998 andGobburu et al. 2001). As indicated in the present clinical trial, theuse of a rivastigmine intranasal spray in accordance with the inventionat a dose, for example, of 2 to 3 sprays twice-daily may delivercomparable rivastigmine exposure and efficacy as a 6 to 9.7 mg/d oraldose and a 10 cm² transdermal patch, respectively (e.g. 9.7 mgoral×F_(oral) 0.602=5.84 mg≈5.84/2.0=2.92 sprays twice-daily) (Winbladet al. 2007, Hossain et al. 2002). Furthermore, an estimated dose of aintranasal spray in accordance with the invention comparable to the 10cm² transdermal patch, may reduce the cholinergic burden exposure by 55%based on the geometric mean AUC exposures for rivastigmine and NAP226-90(i.e. ((21.9×3/99.5)−1)%+((16.7×3/63.8)−1)%=−55%) (Lefèvre et al.2008a). It is considered that removing undesirable cholinergic burden byusing rapid-onset dosing with an intranasal spray in accordance with thepresent invention during waking hours has the potential to allow apatient to move further up the dose-response curve (Imbimbo 2001).

As indicated from abovementioned clinical trial results, a rivastigmineintranasal spray in accordance with the invention may advantageouslyprovide improved absolute bioavailability, rapid onset of action, lowNAP226-90 to rivastigmine exposure ratio, a favourable safety andtolerability profile and/or flexible dosage adjustment.

Example 13: Viscosity of Intranasal Spray Composition

The viscosity of the rivastigmine intranasal spray composition describedin Example 12 was determined using a falling-ball-type viscometer withglass ball (Gilmont, Thermo Scientific, USA). To calculate viscosity,the Viscometer constant (K)=Viscosity in centipoise (cP) divided by[(Density of the glass ball; 2.53 g/cm³−Density of the liquid beingtested; 0.9991 g/cm³ water or 0.9932 g/cm³ Ex.11 composition) ismultiplied by Time of descent in minutes]. The viscosity experiment wasconducted at ambient temperature (15° C.) and ultrapure water was usedto verify the viscometer constant (K) using the known viscosity of waterof 1.1375 cP at 15° C. (IAPWS 2008). Based on two concordantmeasurements of Time of descent, the mean viscosity of the rivastigmineintranasal composition of Example 11 was 1.5 cP at 15° C. (or anestimated 1.2 cP at 25° C.).

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1. A sustained-release aqueous intranasal formulation comprising:rivastigmine tartrate in an amount of from about 0.5% to about 15% byweight of the total formulation; a pH modifying agent in an amount toprovide the formulation with a pH in the range of about 3 to 6; and anasal mucosa tolerant thickening agent in an amount selected to improveadherence of the formulation to the nasal mucosa without adverselyaffecting administration of the formulations as an intranasal spray,said amount being from about 0.1% to about 2% by weight of the totalformulation.
 2. (canceled)
 3. (canceled)
 4. The aqueous formulation ofclaim 1, wherein the pH modifying agent is selected from citrate bufferor citric acid.
 5. The aqueous formulation of claim 1, wherein the pHmodifying agent is present in an amount of from about 0.01% to about 2%by weight of the total formulation.
 6. The aqueous formulation of claim1, wherein the thickening agent is selected from the group consisting ofmethylcellulose, ethylcellulose, hydroxy-ethylcellulose, hydroxyl propylcellulose, hydroxy propyl methylcellulose, sodium carboxymethylcellulose; polyacrylic acid polymers, poly hydroxyethylmethylacrylate; polyethylene oxide; polyvinyl pyrrolidone; polyvinylalcohol, tragacanth, sodium alginate, guar gum, xanthan gum, lectin,soluble starch, gelatin, pectin, and chitosan.
 7. (canceled)
 8. Theaqueous formulation of claim 1, wherein the formulation provides anabsolute bioavailability (F) of rivastigmine equivalent to at least 60%.9. The aqueous formulation of claim 1, further comprising a sensoryagent.
 10. The aqueous formulation of claim 9, wherein the sensory agentis selected from the group comprising a C₂ to C₄ alcohol, menthols,terpenes, thymol, camphor, capsicum, phenol, carveol, mentholglucuronide, eucalyptus oil, benzyl alcohol, salicyl alcohol, ethanol,isopropanol, clove bud oil, mint, spearmint, peppermint, eucalyptus,lavender, citrus, lemon, lime, hexylresorcinol, ketals, diols, andmixtures thereof.
 11. The aqueous formulation of claim 9, wherein thesensory agent is present in an amount of about 1% to about 15% by weightof the total formulation.
 12. The aqueous formulation of claim 1,further comprising an additional therapeutic agent selected from thegroup consisting of a sigma-1 receptor agonist, an NMDA antagonist, anicotinic acetylcholine receptor agonist, and combinations thereof. 13.The aqueous formulation of claim 12, wherein the additional therapeuticagent is selected from the group consisting of dextromethorphan,memantine, ifenprodil, encenicline, or pharmaceutically acceptablederivatives thereof.
 14. A method of treating a neurodegenerativedisease in a mammal, comprising administering the intranasal formulationof claim 1 to a mammal in need thereof.
 15. (canceled)
 16. The method ofclaim 14, wherein the neurodegenerative disease is selected from thegroup consisting of Alzheimer's disease, Parkinson's disease, andcognitive dysfunction syndrome.
 17. The method of claims of claim 14,wherein the absolute bioavailability (F) of rivastigmine is equivalentto at least 60%.
 18. The method of claim 14, wherein the rivastigmineplasma concentration (C_(max)) of the mammal is at least about 5000pg/mL.
 19. The method of claim 14, wherein the therapeutic rivastigmineplasma concentration (C_(ther)) of the mammal is in the range of about2000 pg/mL to about 20,000 pg/mL.
 20. The method of claim 18, whereinthe therapeutic rivastigmine plasma concentration is maintained for aduration of at least 4 hours (T_(maint)).
 21. The method of claim 14,wherein the intranasal administration is associated with a reducedincidence of side effects.
 22. (canceled)
 23. (canceled)
 24. (canceled)25. The formulation of claim 1, wherein the pH modifying agent is citricacid and the thickening agent is polyvinyl pyrrolidone.
 26. Asustained-release aqueous intranasal formulation consisting ofrivastigmine tartrate, citric acid monohydrate, polyvinyl pyrrolidone,ethanol, benzyl alcohol, l-carveol, and water.
 27. A sustained-releaseaqueous intranasal formulation comprising: rivastigmine tartrate in anamount of from about 0.5% to about 15% by weight of the totalformulation; citric acid monohydrate in an amount to provide theformulation with a pH in the range of about 3 to 6; polyvinylpyrrolidone in an amount selected to improve adherence of theformulation to the nasal mucosa without adversely affectingadministration of the formulation as an intranasal spray, said amountbeing from about 0.1% to about 2% by weight of the total formulation;ethanol; benzyl alcohol; l-carveol; and water.